Risk Factors for Early Fungal Disease in Solid Organ Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND: Invasive fungal infections are associated with high morbidity in solid organ transplant recipients. Risk factor modification may help with preventative efforts. The objective of this study was to identify risk factors for the development of fungal infections within the first year following solid organ transplant. METHODS: We searched for eligible articles through February 3, 2023. Studies published after January 1, 2001, that pertained to risk factors for development of invasive fungal infections in solid organ transplant were reviewed for inclusion. Of 3087 articles screened, 58 were included. Meta-analysis was conducted using a random-effects model to evaluate individual risk factors for the primary outcome of any invasive fungal infections and invasive candidiasis or invasive aspergillosis (when possible) within 1 y posttransplant. RESULTS: We found 3 variables with a high certainty of evidence and strong associations (relative effect estimate ≥ 2) to any early invasive fungal infections across all solid organ transplant groups: reoperation (odds ratio [OR], 2.92; confidence interval [CI], 1.79-4.75), posttransplant renal replacement therapy (OR, 2.91; CI, 1.87-4.51), and cytomegalovirus disease (OR, 2.97; CI, 1.78-4.94). Both posttransplant renal replacement therapy (OR, 3.36; CI, 1.78-6.34) and posttransplant cytomegalovirus disease (OR, 2.81; CI, 1.47-5.36) increased the odds of early posttransplant invasive aspergillosis. No individual variables could be pooled across groups for invasive candidiasis. CONCLUSIONS: Several common risk factors exist for the development of any invasive fungal infections in solid organ transplant recipients. Additional risk factors for invasive candidiasis and aspergillosis may be unique to the pathogen, transplanted organ, or both.

Expanded extracorporeal membrane oxygenation bridge to heart and lung transplant candidate selection does not impact outcomes compared to traditional candidate selection criteria.

Extracorporeal membrane oxygenation is used as a bridge to transplant (ECMO-BTT) in selected patients. The objective of this study was to determine whether 1-year post-transplant and post-ECMO survival are impacted by traditional compared to expanded selection criteria. We performed a retrospective study of patients >17 years who received ECMO as bridge to transplant (BTT) or bridge to transplant decision for lung or combined heart and lung transplantation at the Mayo Clinic Florida and Rochester. Institutional protocol excludes patients >55 years, maintained on steroids, unable to participate in physical therapy, with body mass index >30 or <18.5 kg/m2, non-pulmonary end-organ dysfunction, or unmanageable infections from ECMO-BTT. For this study, adherence to this protocol was considered traditional whereas exceptions to the protocol were considered expanded selection criteria. A total of 45 patients received ECMO as bridge therapy. Out of those 29 patients (64%) received ECMO as bridge to transplant and 16 patients (36%) as bridge to transplant decision. The traditional criteria cohort consisted of 15 (33%) patients and expanded criteria cohort consisted of 30 (67%) patients. In the traditional cohort, 9 (60%) of 15 patients were successfully transplanted compared to 16 (53%) of 30 patients in the expanded criteria cohort. No difference in being delisted or dying on the waitlist (OR: 0.58, CI: 0.13-2.58), surviving to 1-year post-transplant (OR: 0.53, CI: 0.03-9.71) or 1-year post-ECMO (OR: 0.77, CI: 0.0.23-2.56) was observed between the traditional criteria and expanded criteria cohorts. At our institution, we did not see differences in odds of 1-year post-transplant and post-ECMO survival between those who met traditional criteria compared to those who did not. Multicenter, prospective studies are needed to evaluate the impact of ECMO-BTT selection criteria.

A Clinician's Guide to Running Custom Machine-Learning Models in an Electronic Health Record Environment.

We recently brought an internally developed machine-learning model for predicting which patients in the emergency department would require hospital admission into the live electronic health record environment. Doing so involved navigating several engineering challenges that required the expertise of multiple parties across our institution. Our team of physician data scientists developed, validated, and implemented the model. We recognize a broad interest and need to adopt machine-learning models into clinical practice and seek to share our experience to enable other clinician-led initiatives. This Brief Report covers the entire model deployment process, starting once a team has trained and validated a model they wish to deploy in live clinical operations.

Digital Health Surveillance Strategies for Management of Coronavirus Disease 2019.

OBJECTIVE: To describe the design, implementation, and utilization of electronic health record (EHR)-based digital health surveillance strategies used to manage the coronavirus disease 2019 (COVID-19) pandemic and to ensure delivery of high-quality clinical care, such as case identification, remote monitoring, telemedicine services, and recruitment to clinical trials at Mayo Clinic. METHODS: The design and implementation work described in this report was performed at Mayo Clinic, a large multistate integrated health care system with more than 1.5 million annual patient visits that uses the Epic EHR system. Rule-based live registries were designed in the EHR system to classify patients who currently test positive for COVID-19, patients who test positive but have recovered from COVID-19, patients who are thought to have COVID-19 but do not yet meet clinical diagnostic criteria, patients who test negative for COVID-19, and patients who exceed a risk score for serious complications from COVID-19. RESULTS: By use of registries, custom dashboards and operational reports were developed to provide a daily high-level summary for clinical practice use and up-to-date information to manage individual patients affected by COVID-19, including support of case identification, contact isolation, and other care management tasks. CONCLUSION: We developed and implemented a systematic approach to the use of EHR patient registries to manage the COVID-19 pandemic that proved feasible and useful in a large multistate group clinical practice. The key to harnessing the potential of digital surveillance tools to promote patient-centered care during the COVID-19 pandemic was to use the registry data, reports, and dashboards as informatics tools to inform decision-making.

Epidemiology, Risk Factors, and Outcomes of Diffuse Alveolar Hemorrhage After Hematopoietic Stem Cell Transplantation.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is an uncommon complication of hematopoietic stem cell transplantation (HCT) that carries high morbidity and mortality. Limited contemporary data are available regarding the incidence, outcomes, and risk factors for DAH. RESEARCH QUESTION: What are the incidence, outcomes, and risk factors for DAH developing after HCT? METHODS: This was a single-center retrospective cohort study of patients who underwent HCT between January 1, 2005, and December 31, 2016. The incidence and outcomes of DAH development were evaluated. A multivariate logistic regression model was used to analyze differences between survivors and nonsurvivors. RESULTS: Of 4,350 patients undergoing first-time HCT, DAH was diagnosed in 99 (2.3%). DAH was seen in 40 of 3,536 autologous HCT recipients (1.1%) and 59 of 814 allogeneic HCT recipients (7.2%). Mean age was 53 ± 13 years, and median time of DAH diagnosis was 126 days (interquartile range, 19-349 days) after HCT. In-hospital mortality and mortality 1 year after DAH diagnosis were 55.6% and 76.8%, respectively. DAH diagnosis more than 30 days after transplantation (OR, 7.06; 95% CI, 1.65-30.14), low platelet count (OR, 0.98; 95% CI, 0.96-1.0; P = .02), elevated international normalized ratio (INR; OR, 4.08; 95% CI, 0.64-25.88; P = .046) and need for invasive mechanical ventilation (OR, 8.18; 95% CI, 1.9-35.21) were associated with higher in-hospital mortality. Steroid treatment did not alter mortality (P = .80) or length of stay (P = .65). However, among those who received steroids, survival was higher in whose who received modest-dose steroids (< 250 mg methylprednisolone equivalent/d) compared with those who received high-dose steroids (≥ 250 mg methylprednisolone equivalent/d; OR, 0.21; 95% CI, 0.07-0.72). INTERPRETATION: The mortality of DAH after HCT remains high, and DAH can occur long after transplantation. Later development of DAH (>30 days after HCT), need for invasive mechanical ventilation, thrombocytopenia, and elevated INR are all associated with worse outcomes.

The Impact of Antifungal Prophylaxis in Lung Transplant Recipients.

Rationale: Many lung transplant centers prescribe antifungal medications after transplantation to prevent invasive fungal infections (IFIs); however, the effectiveness of antifungal prophylaxis at reducing the risk of all-cause mortality or IFI has not been established.Objectives: We aimed to evaluate the effect of antifungal prophylaxis on all-cause mortality and IFI in lung transplant patients.Methods: Using administrative claims data, we identified adult patients who underwent lung transplantation between January 1, 2005, and December 31, 2018. Propensity score analysis using inverse probability treatment-weighting approach was used to balance the differences in baseline characteristics between those receiving antifungal prophylaxis and those not receiving antifungal prophylaxis. Cox proportional hazards regression was used to compare rates of all-cause mortality and IFI in both groups.Results: We identified 662 lung transplant recipients (LTRs) (387 received prophylaxis and 275 did not). All-cause mortality was significantly lower in those receiving antifungal prophylaxis compared with those not receiving antifungal prophylaxis (event rate per 100 person-years, 8.36 vs. 19.49; hazard ratio, 0.43; 95% confidence interval, 0.26-0.71; P = 0.003). Patients receiving antifungal prophylaxis had a lower rate of IFI compared with those not receiving prophylaxis (event rate per 100 person-years, 14.94 vs. 22.37; hazard ratio, 0.68; 95% confidence interval, 0.44-1.05; P = 0.079), but did not reach statistical significance.Conclusions: In this real-world analysis, antifungal prophylaxis in LTRs was associated with reduced all-cause mortality compared with those not receiving antifungal prophylaxis. Rates of IFI were also lower in those receiving prophylaxis, but this was not statistically significant in our primary analysis.

Characteristics and Outcome of Periengraftment Respiratory Distress Syndrome after Autologous Hematopoietic Cell Transplant.

Rationale: The periengraftment respiratory distress syndrome (PERDS) is an early important cause of morbidity following autologous hematopoietic cell transplantation (HCT). There are few contemporary data describing PERDS. Objectives: To determine prevalence, risk factors, and outcomes of PERDS after autologous HCT. Methods: This was a historical cohort study of adults undergoing autologous HCT at Mayo Clinic, Rochester, Minnesota, between 2005 and 2016. PERDS was defined as 1) respiratory failure requiring supplemental oxygen within 5 days on either side of the neutrophil engraftment date, 2) new pulmonary opacities on chest imaging, and 3) exclusion of an infectious or cardiac etiology to explain the clinical presentation. Results: Of 3,473 patients undergoing autologous HCT, 167 (4.8%) developed PERDS. Radiographic changes preceded engraftment in 77% of cases. In a multivariable regression model, risk factors for PERDS included female sex (odds ratio [OR], 1.73; P = 0.001), the number of preengraftment platelet transfusions (OR, 1.22; P = 0.002), and more rapid engraftment (OR, 0.72 per day longer; P < 0.001). PERDS cases were more likely to be admitted to the intensive care unit (47.3% vs. 9.5%, P < 0.001) and require intubation (20.4% vs. 1.6%, P < 0.001). In an adjusted 100-day death analysis, those diagnosed with PERDS were more likely to die (hazard ratio, 3.1; 95% confidence interval, 1.5-6.2; P = 0.002). Conclusions: PERDS is a common complication of autologous HCT and is associated with increased mortality and healthcare use. Radiographic evidence of pulmonary involvement precedes hematopoietic recovery. A larger number of platelet transfusions and more rapid engraftment appear to increase risk for PERDS.

New Billing Rules for Outpatient Office Visit Codes.

Guidelines for clinical documentation of evaluation and management face-to-face services were developed > 20 years ago. Recently, the Centers for Medicare & Medicaid Services (CMS) have addressed office and other outpatient services and the corresponding reimbursement, intending to reduce the amount of required documentation and to alleviate clerical burden. A CMS final rule for 2021 will eliminate the history and physical examination as criteria for level of service, allow time or medical decision-making to be used as coding criteria, and will recognize a code for prolonged service. The net effect of these changes may be some decrease in documentation burden, a change in the composition of clinical notes, and greater recognition by CMS of primary care and those who see highly complex patients requiring prolonged services.

Why do lung transplant patients discontinue triazole prophylaxis?

BACKGROUND: Lung transplant recipients are prone to invasive fungal infections prompting many transplant centers to use prolonged triazole antifungal prophylaxis. From a practical standpoint, it is unclear if lung transplant recipients are able to continue prolonged or lifelong prophylaxis without premature discontinuation from side effects, drug interactions, development of fungal disease, or medication cost. We examined the number of patients that are able to reach a prophylactic endpoint and understand the reasons for early termination. METHODS: We conducted a retrospective chart review of all lung and heart-lung transplant patients at Mayo Clinic Rochester from May 1, 2002 to December 31, 2017. Type, duration, and reason for discontinuation of triazole prophylaxis were examined. RESULTS: During the study period, 193 patients underwent lung or heart-lung transplantation. Itraconazole, voriconazole, and posaconazole were given to 180, 73, and 60 post-transplant patients, respectively. Providers switched itraconazole to another prophylactic antifungal medication for reasons other than prophylactic completion in 61.8% (126 out of 204) of exposure episodes; this was similar with voriconazole (68.8%, 53 out of 77, P = 0.41). Posaconazole was actively discontinued significantly less often (18.3%, 11 out of 60, P < 0.05). The most common reasons for discontinuing itraconazole were malabsorption (15.5% of exposure episodes) and concern for breakthrough fungal infection (10.2%). In comparison, the most common reason for voriconazole discontinuation was side effect or intolerance (54.5% of VR exposure episodes vs 9.8% of IT exposure episodes, P < 0.05). CONCLUSIONS: Itraconazole and posaconazole appeared to have fewer side effects prompting discontinuation than voriconazole, but itraconazole was discontinued more often because of malabsorption and clinical suspicion of fungal infections.

The Diagnostic Yield, Safety, and Impact of Flexible Bronchoscopy in Non-HIV Immunocompromised Critically Ill Patients in the Intensive Care Unit.

BACKGROUND: Flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) have major roles in the evaluation of parenchymal lung diseases in immunocompromised patients. Given the limited evidence, lack of standardized practice, and variable perception of procedural safety, uncertainty still exists on what constitutes the best approach in critically ill patients with immunocompromised state who present with pulmonary infiltrates in the era of prophylactic antimicrobials and the presence of new diagnostic tests. OBJECTIVE: To evaluate the diagnostic yield, safety and impact of FB and BAL on management decisions in immunocompromised critically ill patients admitted to the intensive care unit (ICU). METHODS: A prospective, observational study of 106 non-HIV immunocompromised patients admitted to the intensive care unit with pulmonary infiltrates who underwent FB with BAL. RESULTS: FB and BAL established the diagnosis in 38 (33%) of cases, and had a positive impact on management in 44 (38.3%) of cases. Escalation of ventilator support was not required in 94 (81.7%) of cases, while 18 (15.7%) required invasive and 3 (2.6%) required non-invasive positive pressure ventilation after the procedure. Three patients (2.6%) died within 24 h of bronchoscopy, and 46 patients (40%) died in ICU. Significant hypoxemia developed in 5% of cases. CONCLUSION: FB can be safely performed in immunocompromised critically ill patients in the ICU. The yield can be improved when FB is done prior to initiation of empiric antimicrobials, within 24 h of admission to the ICU, and in patients with focal disease.

Clinical Correlates and Treatment Outcomes for Patients With Short Telomere Syndromes.

Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.

Creation of a Balloon-Expandable Bifurcated Covered Stent to Treat a Complex Left Anastomotic Stricture in a Lung Transplant Recipient.

Airway complications after lung transplant occur in approximately 10-15% of the recipients and often occur at the anastomosis, largely due to ischemia. To decrease anastomotic ischemia, surgeons minimize the length of the donor bronchus. However, a shortened donor bronchus creates technical challenges if a stent is required to treat an airway complication. We present a case of a lung transplant recipient with the combination of left main stem bronchial malacia and a triad of severe strictures at the left anastomosis, entrance to the left upper lobe, and left lower lobe. After failing several attempts using other modalities, success was achieved with in situ creation of a bifurcated fully covered balloon-expandable metallic stent. We describe a novel technique of punching a side branch hole through the wall of the stent to allow a left upper lobe stent to be placed through a stent directed into the left lower lobe in a Y configuration with a good clinical outcome.

Can a Novel ICU Data Display Positively Affect Patient Outcomes and Save Lives?

The aim of this study was to quantify the impact of ProCCESs AWARE, Ambient Clinical Analytics, Rochester, MN, a novel acute care electronic medical record interface, on a range of care process and patient health outcome metrics in intensive care units (ICUs). ProCCESs AWARE is a novel acute care EMR interface that contains built-in tools for error prevention, practice surveillance, decision support and reporting. We compared outcomes before and after AWARE implementation using a prospective cohort and a historical control. The study population included all critically ill adult patients (over 18 years old) admitted to four ICUs at Mayo Clinic, Rochester, MN, who stayed in hospital at least 24 h. The pre-AWARE cohort included 983 patients from 2010, and the post-AWARE cohort included 856 patients from 2014. We analyzed patient health outcomes, care process quality, and hospital charges. After adjusting for patient acuity and baseline demographics, overall in-hospital and ICU mortality odds ratios associated with AWARE intervention were 0.45 (95% confidence interval 0.30 to 0.70) and 0.38 (0.22, 0.66). ICU length of stay decreased by about 50%, hospital length of stay by 37%, and total charges for hospital stay by 30% in post AWARE cohort (by $43,745 after adjusting for patient acuity and demographics). Better organization of information in the ICU with systems like AWARE has the potential to improve important patient outcomes, such as mortality and length of stay, resulting in reductions in costs of care.

Effect of a Novel Clinical Decision Support Tool on the Efficiency and Accuracy of Treatment Recommendations for Cholesterol Management.

BACKGROUND: The 2013 American College of Cardiology / American Heart Association Guidelines for the Treatment of Blood Cholesterol emphasize treatment based on cardiovascular risk. But finding time in a primary care visit to manually calculate cardiovascular risk and prescribe treatment based on risk is challenging. We developed an informatics-based clinical decision support tool, MayoExpertAdvisor, to deliver automated cardiovascular risk scores and guideline-based treatment recommendations based on patient-specific data in the electronic heath record. OBJECTIVE: To assess the impact of our clinical decision support tool on the efficiency and accuracy of clinician calculation of cardiovascular risk and its effect on the delivery of guideline-consistent treatment recommendations. METHODS: Clinicians were asked to review the EHR records of selected patients. We evaluated the amount of time and the number of clicks and keystrokes needed to calculate cardiovascular risk and provide a treatment recommendation with and without our clinical decision support tool. We also compared the treatment recommendation arrived at by clinicians with and without the use of our tool to those recommended by the guidelines. RESULTS: Clinicians saved 3 minutes and 38 seconds in completing both tasks with MayoExpertAdvisor, used 94 fewer clicks and 23 fewer key strokes, and improved accuracy from the baseline of 60.61% to 100% for both the risk score calculation and guideline-consistent treatment recommendation. CONCLUSION: Informatics solution can greatly improve the efficiency and accuracy of individualized treatment recommendations and have the potential to increase guideline compliance.

Azithromycin for the Treatment of Obliterative Bronchiolitis after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

Obliterative bronchiolitis (OB) is a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Our objective was to perform a systematic review and meta-analysis of the impact of azithromycin on change in forced expiratory volume in 1 second (FEV1). We searched MEDLINE, EMBASE, Web of Science, Cochrane CENTRAL and Scopus databases and included studies that compared azithromycin with placebo or no intervention in the treatment of OB or bronchiolitis obliterans syndrome (BOS) in patients who had undergone allogeneic HSCT. Ninety-one unique publications were identified, and 4 studies met inclusion criteria, with a total of 90 patients. Changes in FEV1 were measured between 12 and 24 weeks after initiation of treatment. The meta-analysis demonstrated a mean increase in FEV1 of 30 mL (95% confidence interval, -260 to +330 mL; P = .82) after initiation of azithromycin. One patient death was reported but not attributed to azithromycin therapy. In conclusion, current evidence can neither support nor refute the use of azithromycin in the treatment of patients who develop OB/BOS after HSCT. Further studies are needed to determine whether azithromycin is beneficial for the treatment of OB/BOS in this setting.

Epidemiology of Acute Respiratory Distress Syndrome Following Hematopoietic Stem Cell Transplantation.

OBJECTIVES: Pulmonary complications are common following hematopoietic stem cell transplantation. Numerous idiopathic post-transplantation pulmonary syndromes have been described. Patients at the severe end of this spectrum may present with hypoxemic respiratory failure and pulmonary infiltrates, meeting criteria for acute respiratory distress syndrome. The incidence and outcomes of acute respiratory distress syndrome in this setting are poorly characterized. DESIGN: Retrospective cohort study. SETTING: Mayo Clinic, Rochester, MN. PATIENTS: Patients undergoing autologous and allogeneic hematopoietic stem cell transplantation between January 1, 2005, and December 31, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were screened for acute respiratory distress syndrome development within 1 year of hematopoietic stem cell transplantation. Acute respiratory distress syndrome adjudication was performed in accordance with the 2012 Berlin criteria. In total, 133 cases of acute respiratory distress syndrome developed in 2,635 patients undergoing hematopoietic stem cell transplantation (5.0%). Acute respiratory distress syndrome developed in 75 patients (15.6%) undergoing allogeneic hematopoietic stem cell transplantation and 58 patients (2.7%) undergoing autologous hematopoietic stem cell transplantation. Median time to acute respiratory distress syndrome development was 55.4 days (interquartile range, 15.1-139 d) in allogeneic hematopoietic stem cell transplantation and 14.2 days (interquartile range, 10.5-124 d) in autologous hematopoietic stem cell transplantation. Twenty-eight-day mortality was 46.6%. At 12 months following hematopoietic stem cell transplantation, 89 patients (66.9%) who developed acute respiratory distress syndrome had died. Only 7 of 133 acute respiratory distress syndrome cases met criteria for engraftment syndrome and 15 for diffuse alveolar hemorrhage. CONCLUSIONS: Acute respiratory distress syndrome is a frequent complication following hematopoietic stem cell transplantation, dramatically influencing patient-important outcomes. Most cases of acute respiratory distress syndrome following hematopoietic stem cell transplantation do not meet criteria for a more specific post-transplantation pulmonary syndrome. These findings highlight the need to better understand the risk factors underlying acute respiratory distress syndrome in this population, thereby facilitating the development of effective prevention strategies.