Invasive aspergillosis in liver transplant recipients in the current era.

Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multicenter 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in 8 cases (13%). Twelve-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotic usage (adjusted odds ratio [aOR], 4.74; P = .03) and history of pneumonia (aOR, 48.7; P = .01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; P = .01), systemic antibiotic usage (aOR, 5.03; P = .04), and antimold prophylaxis (aOR, 11.9; P = .02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergillus colonization (adjusted hazard ratio [aHR], 86.9; P < .001), intensive care unit stay (aHR, 3.67; P = .02), disseminated IA (aHR, 8.98; P < .001), and dialysis (aHR, 2.93; P = .001) were identified as independent risk factors associated with 12-week all-cause mortality, while recent receipt of tacrolimus (aHR, 0.11; P = .001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted antimold prophylactic and appropriate treatment strategies against IA.

Epidemiology of candidemia in lung transplant recipients and risk factors for candidemia in the early posttransplant period in the absence of universal antifungal prophylaxis.

BACKGROUND: Lung transplant recipients are at increased risk of candidemia, especially in the early posttransplant period. However, the specific predisposing factors have not been established. The natural history of candidemia after lung transplantation, in the absence of universal antifungal prophylaxis, is not known. METHODS: We retrospectively examined the epidemiology of candidemia at any time posttransplant in patients who underwent lung transplantation at our center between 2016 and 2019. We undertook a case-control study and used logistic regression to evaluate the risk factors for candidemia during the first 30 days posttransplantation. RESULTS: During the study period 712 lung transplants were performed on 705 patients. Twenty-five lung transplant recipients (LTRs) (3.5%) experienced 31 episodes of candidemia. The median time to candidemia was 19.5 days (IQR 10.5-70.5), with 61.2% (n = 19) episodes of candidemia occurring within the first 30 days posttransplantation. Pretransplant hospitalization, posttransplant ECMO, and posttransplant renal replacement therapy were associated with an increased risk of candidemia in the first 30 days posttransplant. Of those with candidemia in the first 30 days, 31.2% died within 30 days of the index positive blood culture. Candidemia was associated with decreased survival within 30 days posttransplant. CONCLUSION: This study highlights the greatest risk period of lung transplant recipients for development of candidemia and identifies several factors associated with increased risk of candidemia. These findings will help guide future studies on antifungal prophylaxis.

Effect of Therapeutic Drug Monitoring and Cytochrome P450 2C19 Genotyping on Clinical Outcomes of Voriconazole: A Systematic Review.

OBJECTIVES: To examine current knowledge on the clinical utility of therapeutic drug monitoring (TDM) in voriconazole therapy, the impact of CYP2C19 genotype on voriconazole plasma concentrations, and the role of CYP2C19 genotyping in voriconazole therapy. DATA SOURCES: Three literature searches were conducted for original reports on (1) TDM and voriconazole outcomes and (2) voriconazole and CYP2C19 polymorphisms. Searches were conducted through EMBASE, MEDLINE/PubMed, Scopus, and Cochrane Central Register of Controlled Trials from inception to June 2020. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials, cohort studies, and case series with ≥10 patients were included. Only full-text references in English were eligible. DATA SYNTHESIS: A total of 63 studies were reviewed. TDM was recommended because of established concentration and efficacy/toxicity relationships. Voriconazole trough concentrations ≥1.0 mg/L were associated with treatment success; supratherapeutic concentrations were associated with increased neurotoxicity; and hepatotoxicity associations were more prevalent in Asian populations. CYP2C19 polymorphisms significantly affect voriconazole metabolism, but no relationship with efficacy/safety were found. Genotype-guided dosing with TDM was reported to increase chances of achieving therapeutic range. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Genotype-guided dosing with TDM is a potential solution to optimizing voriconazole efficacy while avoiding treatment failures and common toxicities. CONCLUSIONS: Voriconazole plasma concentrations and TDM are treatment outcome predictors, but research is needed to form a consensus target therapeutic range and dosage adjustment guidelines based on plasma concentrations. CYP2C19 polymorphisms are a predictor of voriconazole concentrations and metabolism, but clinical implications are not established. Large-scale, high-methodological-quality trials are required to investigate the role for prospective genotyping and establish CYP2C19-guided voriconazole dosing recommendations.

Clinical and economic burden of infections in hospitalized solid organ transplant recipients compared with the general population in Canada - a retrospective cohort study.

Infections continue to be a major cause of post-transplant morbidity and mortality, requiring increased health services utilization. Estimates on the magnitude of this impact are relatively unknown. Using national administrative databases, we compared mortality, acute care health services utilization, and costs in solid organ transplant (SOT) recipients to nontransplant patients using a retrospective cohort of hospitalizations in Canada (excluding Manitoba/Quebec) between April-2009 and March-2014, with a diagnosis of pneumonia, urinary tract infection (UTI), or sepsis. Costs were analyzed using multivariable linear regression. We examined 816 324 admissions in total: 408 352 pneumonia; 328 066 UTI's; and 128 275 sepsis. Unadjusted mean costs were greater in SOT compared to non-SOT patients with pneumonia [(C$14 923 ± C$29 147) vs. (C$11 274 ± C$18 284)] and sepsis [(C$23 434 ± C$39 685) vs. (C$20 849 ± C$36 257)]. Mortality (7.6% vs. 12.5%; P < 0.001), long-term care transfer (5.3% vs. 16.5%; P < 0.001), and mean length of stay (11.0 ± 17.7 days vs. 13.1 ± 24.9 days; P < 0.001) were lower in SOT. More SOT patients could be discharged home (63.2% vs. 44.3%; P < 0.001), but required more specialized care (23.5% vs. 16.1%; P < 0.001). Adjusting for age and comorbidities, hospitalization costs for SOT patients were 10% (95% CI: 8-12%) lower compared to non-SOT patients. Increased absolute hospitalization costs for these infections are tempered by lower adjusted costs and favorable clinical outcomes.

Clinical and microbiological epidemiology of early and late infectious complications among solid-organ transplant recipients requiring hospitalization.

There is limited literature describing the clinical and microbiological characteristics of solid-organ transplant recipients requiring hospitalization for infectious complications. This study reports on the rate and timing of these syndromes and describes the associated microbiological epidemiology. This prevalence cohort study evaluated solid-organ transplant recipients requiring hospitalization during 2007-2011. We reported infectious complications requiring hospitalization in 603 of 1414 readmissions at a rate of 0.43 episodes per 1000 transplant-days (95% CI, 0.40-0.47), with 85% occurring >6 months post-transplantation. The most frequent infectious complications were as follows: respiratory (27%), sepsis or bacteremia (13%), liver or biliary tract (12%), genitourinary (12%), and cytomegalovirus related (9%). Approximately 53% presented without fever, 45% had no pathogen isolated, and multidrug-resistant organisms were isolated in 27% of those with an identified microbiological etiology. Infectious-related complications continue to pose a high clinical burden on our acute care center, with the majority occurring in the late transplant period. Clinicians are faced with the difficult task of prescribing adequate antimicrobial therapy.

Impact of infectious disease consultation on the clinical and economic outcomes of solid organ transplant recipients admitted for infectious complications.

BACKGROUND: There has been a paucity of data on the healthcare resource utilization of infectious disease-related complications in solid organ transplant recipients. The aims of this study were to report the clinical and economic burden of infectious disease-related complications, along with the impact of infectious disease consultation. METHODS: This cohort study evaluated patients requiring admission to a tertiary-care center during 2007, 2008, and 2011. Propensity score matching was used to estimate the effects of patient demographics, comorbidities, and transplant- and infection-related factors on 28-day hospital survival, length of stay (LOS), and medical costs. RESULTS: Infectious disease-related complications occurred in 603 of 1414 (43%) admissions in 306 of 531 (58%) patients. Unadjusted 28-day mortality did not differ between those who received infectious disease consultations vs those who did not (2.9% vs 3.6%, P = .820), however, after propensity score matching, infectious disease consultation resulted in significantly greater 28-day survival estimates (hazard ratio = 0.33; log-rank P = .026), and reduced 30-day rehospitalization rates (16.9% vs 23.9%, P = .036). The median LOS and hospitalization costs were significantly increased for patients receiving an infectious disease consultation than in those managed by the attending team alone (7.0 vs 5.0 days, P = .002, and $9652 vs $6192, P = .003). However, the median LOS (5.5 vs 5.1 days, P = .31) and hospitalization costs ($8106 vs $6912, P = .63) did not differ significantly among those receiving an early infectious disease consultation (<48 hours) vs no consultation, respectively. CONCLUSIONS: Infectious disease consultation in recipients of solid organ transplant is associated with increased LOS and hospitalization costs but decreased mortality and reduced rehospitalization rates. Early consultation with infectious disease specialists decreases healthcare resource utilization compared with delayed referrals.

A Systematic Review and Meta-Analysis of the Cancer.

OBJECTIVE: Prostate cancer is the second- leading cause of cancer death among men. We aimed to evaluate high-intensity focused ultrasound (HIFU), open radical prostatectomy (ORP), robot-assisted radical prostatectomy (RARP), and external beam radiation therapy (RT) in the treatment of localized low- and intermediate-risk prostate cancer. METHODS: We searched bibliographic databases for case-control, cohort, and randomized controlled studies. We used MeSH subject headings and free text terms for prostate cancer, HIFU, ORP, RARP, RT, failure-free survival (FFS), biochemical disease-free survival (BDFS), urinary incontinence (UI), and erectile dysfunction (ED). RESULTS: Fourteen studies were included in the review, for a total of 34 927 participants. Among the 8 studies of HIFU as the primary treatment of localized low- and intermediate- risk prostate cancer, 4 studies reported 5-year FFS rates ranging from 67.8% to 97.8%, 3 studies reported 5-year BDFS ranging from 58% to 85.4%, 5 studies reported 1-year UI rates ranging from 0% to 6%, and 4 studies reported 1-year ED rates ranging from 11.4% to 38.7%. Furthermore, our search revealed a 5-year FFS benefit favoring ORP compared to RT, a 1-year UI rate favoring ORP compared to RARP, and a 1-year ED rate favoring ORP compared to RARP. CONCLUSION: Our systematic review and meta-analysis revealed lack of studies with active comparators comparing HIFU to standard of care (ORP, RARP, or RT) in primary treatment of localized low- and intermediate-risk prostate cancer. Open radical prostatectomy has favorable efficacy outcomes compared to RT, while RARP has beneficial functional outcomes compared to ORP, respectively.

Pilot study of a pharmaceutical care intervention in an outpatient lung transplant clinic.

BACKGROUND: Lung transplant recipients have complex drug regimens. Study objectives were to assess drug therapy problems (DTPs), pharmacist recommendations, and patient satisfaction with pharmacist services. METHODS: Using a pharmaceutical care assessment process, pharmacists identified DTPs and made therapeutic recommendations. Number of DTPs identified per pharmacist visit was calculated and compared to standard care visits through retrospective chart review. Potential clinical impact of recommendations was evaluated by blinded clinicians. Patient satisfaction was assessed via survey. RESULTS: Fifty-five DTPs were identified in 43 patients over 50 pharmacist visits (1.05 ± 1.34 DTPs per visit). In these same patients, rate of DTP identification was 0.51 ± 0.64 DTPs per standard visit in the preceding two-wk period (p = 0.018 vs. pharmacist visit). The most common DTPs identified by the pharmacist were adverse drug effect (27%) and untreated indication (25%). Overall, 62% of pharmacist recommendations were rated very significant or significant. Survey return rate was 58% and satisfaction scores ranged from 3 to 5 out of 5. Review of medications and teaching regarding the use of medications received the most "very satisfied" and "highly important" scores. CONCLUSIONS: Pharmacists can make valuable contributions in a lung transplant clinic setting by identifying DTPs and making recommendations with a positive impact on patient outcomes and satisfaction.

Opioid Utilization and Management in the Setting of Stewardship During Inpatient Rehab Care.

Background: Opioid utilization and management in an inpatient rehabilitation setting have not been widely described, despite the unique opportunities that exist in this setting to support opioid stewardship across transitions in care. We aimed to characterize opioid utilization and management by interprofessional teams across a large, inpatient rehabilitation setting after incorporation of opioid stewardship principles by pharmacists as part of their daily practice. Patients and methods: This was a retrospective chart review at Toronto Rehab, University Health Network, Toronto, Canada. Patients with admission orders for any opioid from November 2017 to February 2018 were included. Complex continuing care and palliative care patients were excluded. Descriptive statistics were primarily used to describe the data as well as univariate linear regression to compare associations with milligram morphine equivalent (MME) reduction. Results: A total of 448 patients were included. A reduction in total daily MME was seen in 49% (n=219) of the patients during their inpatient stay, with 73% (n=159) of these patients having a reduction of ≥50%. Sixty-nine percent (n=311) of the patients received an opioid prescription at discharge, with most scheduled (90%, n=98) with a supply of less than 30 days. Rehabilitation length of stay was correlated with a MME decrease during rehab (p<0.01), suggesting that longer lengths of stay contributed to a greater reduction in MME. Patients with chronic opioid use prior to acute care admission (p=0.01), and those who started extended-release opioids during acute care (p=0.02) were significantly less likely to discontinue opioids during rehab stay. Conclusion: Opioid utilization and management in the setting of opioid stewardship across inpatient rehab and transitions of care were characterized. Opportunities exist for further quality improvement initiatives within inpatient rehabilitation and acute care settings to identify and support patients with complex pain management needs.

Medication reconciliation during internal hospital transfer and impact of computerized prescriber order entry.

BACKGROUND: Internal hospital transfer is a vulnerable time during which patients are at high risk of medication discrepancies that can result in clinically significant harm, medication errors, and adverse drug events. OBJECTIVE: To identify, characterize, and assess the clinical impact of unintentional medication discrepancies during internal hospital transfer and to investigate the influence of computerized prescriber order entry (CPOE) on medication discrepancies. METHODS: All patients transferred between 10 inpatient units at 2 tertiary care hospitals were prospectively assessed to identify discrepancies. Interfaces included transfers between (1) units that both used paper-based medication ordering systems; (2) units that both used CPOE-based systems; and (3) units that used both paper-based and CPOE-based systems (hybrid transfer). The primary endpoint was the number of patients with at least 1 unintentional medication discrepancy during internal hospital transfer. Discrepancies were identified through assessment and comparison of a best possible medication transfer list with the actual transfer orders. A multidisciplinary team of clinicians assessed the potential clinical impact and severity of unintentional discrepancies. RESULTS: Overall, 190 patients were screened and 129 patients were included. Eighty patients (62.0%) had at least 1 unintentional medication discrepancy at the time of transfer, and the most common discrepancy was medication omission (55.6%). Factors that independently increased the risk of a patient experiencing at least 1 unintentional discrepancy included lack of best possible medication history, increasing number of home medications, and increasing number of transfer medications. Forty-seven patients (36.4%) had at least 1 unintentional discrepancy with the potential to cause discomfort and/or clinical deterioration. The risk of discrepancies was present regardless of the medication-ordering system (paper, CPOE, or hybrid). CONCLUSIONS: Clinically significant medication discrepancies occur commonly during internal hospital transfer. A structured, collaborative, and clearly defined medication reconciliation process is needed to prevent internal transfer discrepancies and patient harm.

An integrated review of "unplanned" dialysis initiation: reframing the terminology to "suboptimal" initiation.

BACKGROUND: Ideally, care prior to the initiation of dialysis should increase the likelihood that patients start electively outside of the hospital setting with a mature arteriovenous fistula (AVF) or peritoneal dialysis (PD) catheter. However, unplanned dialysis continues to occur in patients both known and unknown to nephrology services, and in both late and early referrals. The objective of this article is to review the clinical and socioeconomic outcomes of unplanned dialysis initiation. The secondary objective is to explore the potential cost implications of reducing the rate of unplanned first dialysis in Canada. METHODS: MEDLINE and EMBASE from inception to 2008 were used to identify studies examining the clinical, economic or quality of life (QoL) outcomes in patients with an unplanned versus planned first dialysis. Data were described in a qualitative manner. RESULTS: Eight European studies (5,805 patients) were reviewed. Duration of hospitalization and mortality was higher for the unplanned versus planned population. Patients undergoing a first unplanned dialysis had significantly worse laboratory parameters and QoL. Rates of unplanned dialysis ranged from 2449%. The total annual burden to the Canadian healthcare system of unplanned dialysis in 2005 was estimated at $33 million in direct hospital costs alone. Reducing the rate of unplanned dialysis by one-half yielded savings ranging from $13.3 to $16.1 million. CONCLUSION: The clinical and socioeconomic impact of unplanned dialysis is significant. To more consistently characterize the unplanned population, the term suboptimal initiation is proposed to include dialysis initiation in hospital and/or with a central venous catheter and/or with a patient not starting on their chronic modality of choice. Further research and implementation of initiatives to reduce the rate of suboptimal initiation of dialysis in Canada are needed.

Lack of association of Aspergillus colonization with the development of bronchiolitis obliterans syndrome in lung transplant recipients: An international cohort study.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS. METHODS: Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders. RESULTS: A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007). CONCLUSIONS: We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS.

Clinical risk factors for invasive aspergillosis in lung transplant recipients: Results of an international cohort study.

BACKGROUND: Invasive aspergillosis (IA) is a frequent complication in lung transplant recipients (LTRs). Clinical risk factors for IA have not been fully characterized, especially in the era of extensive anti-fungal prophylaxis. The primary objective of this study was to evaluate the clinical risk factors associated with IA in LTRs. The secondary objective was to assess the mortality in LTRs who had at least 1 episode of IA compared with LTRs who never had experienced IA. METHODS: We conducted an international, multicenter, retrospective cohort study of 900 consecutive adults who received lung transplants between 2005 and 2008 with 4years of follow-up. Risk factors associated with IA were identified using univariate and multiple regression Cox proportional hazards models. RESULTS: Anti-fungal prophylaxis was administered to 61.7% (555 of 900) of patients, and 79 patients developed 115 episodes of IA. The rate to development of the first episode was 29.6 per 1,000 person-years. Aspergillus fumigatus was the most common species isolated (63% [72 of 115 episodes]). Through multivariate analysis, significant risk factors identified for IA development were single lung transplant (hazard ratio, 1.84; 95% confidence interval, 1.09-3.10; p = 0.02,) and colonization with Aspergillus at 1 year post-transplantation (hazard ratio, 2.11; 95% confidence interval, 1.28-3.49; p = 0.003,). Cystic fibrosis, pre-transplant colonization with Aspergillus spp, and use of anti-fungal prophylaxis were not significantly associated with the development of IA. Time-dependent analysis showed IA was associated with higher mortality rates. CONCLUSION: Incidence of IA remains high in LTRs. Single-lung transplant and airway colonization with Aspergillus spp. within 1 year post-transplant were significantly associated with IA.

Randomized Controlled Trial of a Computer-Based Education Program in the Home for Solid Organ Transplant Recipients: Impact on Medication Knowledge, Satisfaction, and Adherence.

BACKGROUND: De novo solid organ transplant recipients (SOTR) have a steep learning curve to acquire medication knowledge. Without adequate knowledge, SOTR are at risk of nonadherence and poor transplant outcomes. METHODS: In this nonblinded, randomized controlled trial, de novo SOTR received standard teaching with or without postdischarge computer-based education (CBE) at home. Primary outcomes were change in knowledge (quiz and recall) and satisfaction, assessed by questionnaires at baseline and 3 months. Adherence was evaluated via self-report and immunosuppressant levels. RESULTS: Two hundred forty-six patients were randomized and 209 completed the 3-month analysis. In the intervention arm, 73 (57.9%) used the CBE program. Change in knowledge quiz score did not differ between groups (4.9% vs 0.6%; P = 0.084), despite a significant increase within the intervention (72.4% vs 77.3%, P = 0.007) but not the control (76.0% vs 76.6%, P = 0.726) arms. Both groups had a significant improvement in recall (intervention, 56.7% vs 82.1%, P < 0.001; control, 51.3% vs 79.7%, P < 0.001), with similar changes in scores (25.4% vs 28.4%, P = 0.55). Change in satisfaction differed between groups (intervention, 1.2% vs control, -4.9%; P = 0.050). There was a significant decline in satisfaction within the control group (88.4% vs 83.5%, P = 0.035), whereas satisfaction was maintained with the intervention (85.6% vs 86.8%, P = 0.55). Adherence was similar in both groups. CONCLUSIONS: Knowledge improved over the study period in both groups, with no incremental benefit for the intervention. Patient satisfaction was maintained with the CBE program. More research is needed to identify barriers to uptake of CBE at home and to develop effective strategies for posttransplant education.

Timing of rabbit antithymocyte globulin induction therapy in kidney transplantation: an observational cohort study.

BACKGROUND: Literature on the timing of rabbit antithymocyte globulin (rATG) induction and its effects on kidney transplant outcomes is limited. The manufacturer recommends that the first dose be given intra-operatively, however this may present clinical practice risks and challenges. Our objective was to assess the impact of the timing of the first dose of rATG on kidney transplant outcomes. METHODS: Incident kidney transplant recipients (KTR) from January 2002 to December 2009 receiving the first dose of rATG post-operatively (Post, n = 353) or before reperfusion (Pre, n = 124) were evaluated. Outcomes assessed included eGFR at 1-year, delta eGFR (12 versus 1 month), and incidence of biopsy-proven acute rejection, graft loss, death, and a composite of the time-to-event outcomes. The impact of timing on outcomes was adjusted for potential confounders and assessed using linear and Cox regression models. RESULTS: Among 435 KTR surviving with function to 12 months post-transplant, there was no significant difference in mean estimated glomerular filtration rate or eGFR (55.0 versus 56.7 mL/min, P = 0.46) and delta eGFR (1.8 versus 0.3 mL/min, P = 0.40) in Post versus Pre groups, respectively. At a median follow-up of 3 years, the composite endpoint (time to first biopsy-proven acute rejection, graft loss, or death) was similar by timing group (adjusted HR = 0.94; 95% CI: 0.58, 1.53, P = 0.81) in the total study population. CONCLUSIONS: Timing of rATG had no appreciable impact on clinically relevant endpoints in this study cohort. These results support consideration of more flexible timing of the first dose of rATG induction in KTR.