Lahr, Brian

AbstractThe contrasting outcomes of lymphocyte manipulation after solid organ transplantation are allograft rejection and infections, commonly with cytomegalovirus (CMV). Peripheral blood absolute lymphocyte count (ALC) may serve as a predictive marker for these outcomes. Using a retrospective review of clinical and laboratory dataset, we aimed to determine whether a range of ALC (termed “safe ALC corridor”) exists where CMV infection and rejection outcomes are minimal in a cohort of 381 kidney transplant recipients. In an extended Cox model using a time‐dependent covariate for peripheral blood ALC, a value below the cut‐off of 610 cells/uL was associated with the development of CMV infection both in the overall cohort (Hazard Ratio [HR] 2.25 (95% confidence internal [CI] 1.02‐4.96; P = .043) and the subgroup of high‐risk CMV D+/R‐ mismatch patients (HR 2.91 [95% CI 1.09‐7.77]; P = .033). In contrast, a time‐dependent Cox analysis did not show any significant association between ALC and rejection (per IQR decrease, HR 1.2 [95% CI: 0.76‐1.9]; P = .434). Accordingly, a “safe ALC corridor” could not be defined. In conclusion, a low peripheral blood ALC (ie, threshold of 610 cells/uL) can be used to stratify the risk of CMV disease after kidney transplantation.

Abstract Background Infective endocarditis (IE) is the most feared complication of Staphylococcus aureus bacteremia (SAB). Transesophageal echocardiogram (TEE) is generally recommended for all patients with SAB; however, supporting data for this are limited. We previously developed a scoring system, “PREDICT,” that quantifies the risk of IE and identifies patients who would most benefit most from undergoing TEE. The current prospective investigation aims to validate this score. Methods We prospectively screened all consecutive adults (≥18 years) hospitalized with SAB at 3 Mayo Clinic sites between January 2015 and March 2017. Results Of 220 patients screened, 199 with SAB met study criteria and were included in the investigation. Of them, 23 (11.6%) patients were diagnosed with definite IE within 12 weeks of initial presentation based on modified Duke’s criteria. Using the previously derived PREDICT model, the day 1 score of ≥4 had a sensitivity of 30.4% and a specificity of 93.8%, whereas a day 5 score of ≤2 had a sensitivity and negative-predictive value of 100%. Additional factors including surgery or invasive procedure in the past 30 days, prosthetic heart valve, and higher number of positive blood culture bottles in the first set of cultures were associated with increased risk of IE independent of the day 5 risk score. Conclusions We validated the previously developed PREDICT scoring tools for stratifying risk of IE, and the need for undergoing a TEE, among cases of SAB. We also identified other factors with predictive potential, although larger prospective studies are needed to further evaluate possible enhancements to the current scoring system.

Abstract Background: Most trials of standard heparin and warfarin therapy used the 3- to 6-month cumulative incidence of venous thromboembolism (VTE) recurrence as the primary efficacy outcome. Consequently, the effect of heparin anticoagulation intensity on short-term VTE recurrence after controlling for other predictors of recurrence (e.g., active cancer, neurological disease with extremity paresis) is uncertain. Objectives: To test standard heparin anticoagulation intensity, using activated partial prothrombin time (APTT) data, as an independent predictor of 14-day VTE recurrence. Measurements: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis or pulmonary embolism over the 14-year period, 1984–1997 (n=1165). We followed each case (conditional on surviving one day) forward in time through their complete medical records in the community for first VTE recurrence. We collected date of incident VTE onset, start and stop dates of heparin and warfarin, and date, time and result of all APTT and platelet count values. Using these and other measures of standard heparin therapy as time-dependent variables, we tested the intensity of heparin anticoagulation as an independent predictor of 14-day VTE recurrence while controlling for other baseline characteristics using Cox proportional hazards modeling. Results: Of the 1165 patients, 1026 (88%) and 989 (85%) received heparin and warfarin, respectively, and 254 (22%) developed recurrent VTE over 5461 person-years of follow-up; 23 recurred within 14 days. In the multivariate analysis, the independent predictors of 14-day recurrence included female gender (HR=3.06, 95%CI: 1.05, 8.91; p=0.04) and neurologic disease with extremity paresis (HR=6.01, 95%CI: 1.93, 18.66; p<0.01); the hazard of recurrence was marginally increased for active cancer (HR=2.21, p=0.13). Warfarin therapy (HR=0.44, p=0.11) and a therapeutic APTT within the first 24 hours of therapy (HR=0.41, p=0.08) were marginally protective, but age, body mass index, time interval between VTE onset and start of heparin, and other measures of heparin anticoagulation intensity (e.g., proportion of time in therapeutic APTT range, etc) were not predictors of recurrence. Three patients developed new and persistent thrombocytopenia beginning 2, 4 and 5 days after starting heparin, respectively and prior to VTE recurrence. Conclusions: VTE recurrence is uncommon within 14 days after starting heparin therapy. Female gender and neurologic disease with extremity paresis are independent predictors of 14-day recurrence, and active cancer may be an additional predictor. Warfarin therapy and a therapeutic APTT within the first 24 hours may predict a reduced recurrence risk. However, other measures of heparin anticoagulation intensity were non-predictive. Heparin-induced thrombocytopenia may partially account for early VTE recurrence.

Abstract Background: Most trials of standard heparin and warfarin therapy used the 3- to 6-month cumulative incidence of venous thromboembolism (VTE) recurrence as the primary efficacy outcome. However, the independent effect of warfarin anticoagulation intensity on VTE recurrence after controlling for other predictors of recurrence (e.g., active cancer, neurological disease with extremity paresis) is uncertain. Objectives: To test warfarin anticoagulation intensity, using international normalized ratio (INR) data, as an independent predictor of 6-month VTE recurrence. Measurements: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis or pulmonary embolism over the 14-year period, 1984–1997 (n=1165). We followed each case (conditional on surviving 14 days without VTE recurrence) forward in time through their complete medical records in the community for first VTE recurrence. We collected date of incident VTE onset, start and stop dates of heparin and warfarin, and date, time and result of all INR values. Using these and other measures of standard warfarin therapy as time-dependent variables, we tested the intensity of warfarin anticoagulation (expressed as the cumulative percent of time with an INR at or above 2.0 [or at or above 1.5] while on warfarin) as an independent predictor of 6-month VTE recurrence while controlling for other baseline characteristics using Cox proportional hazards modeling. Results: Of the 1165 patients, 1026 (88%) and 989 (85%) received heparin and warfarin, respectively, and 254 (22%) developed recurrent VTE over 5461 person-years of follow-up; 52 recurred within 15–180 days. In the multivariate analysis, the independent predictor of 6-month recurrence was active cancer (HR=3.98, 95% CI: 2.12, 7.45; p<0.01); age, gender, body mass index and neurologic disease with extremity paresis were not predictors of VTE recurrence. In models that included presence or absence of warfarin therapy along with proportion of time with an INR ≥2, this latter intensity variable was protective (HR=0.16 for 100% versus 0% of time, p=0.02) against recurrence, while mere presence of warfarin therapy (HR =0.72, p= 0.56) was not. Similar results were obtained when intensity was represented as proportion of time with an INR ≥1.5 (HR=0.17, p=0.02). Interestingly, a therapeutic APTT within the first 24 hours of heparin therapy also was protective against 6-month recurrence (HR=0.45, p=0.02). Conclusions: Active cancer is an independent predictor of 6-month VTE recurrence. Warfarin therapy with a higher proportion of time with an INR ≥1.5 or ≥2 offers similar protection against recurrence. A rapid heparin-response (as reflected by a therapeutic APTT within 24 hours of heparin therapy) also is a predictor of reduced 6-month recurrence, possibly reflecting lower factor VIII activity at the acute incident VTE event. Gender is not a predictor of long-term recurrence.

BackgroundSurgical exclusion of the left atrial appendage (LAA) can be performed at the time of cardiac operation as a potential modality to decrease cardioembolic risk attributable to atrial fibrillation (AF), but it remains unclear if this decreases stroke incidence. Furthermore, it is not known whether LAA exclusion impacts the decision to discontinue anticoagulation impacting subsequent stroke risk.HypothesisLAA exclusion does not significantly alter subsequent anticoagulation use or stroke incidence.MethodsWe studied 124 patients from Olmsted County with prior history of AF who underwent cardiac surgery at our institution between 1993 and 2015. Patients were divided into two groups on the basis of LAA exclusion and matched (1:1) according to 16 pretreatment variables using propensity scores obtained from a logistic regression model. Outcome data collected through chart review for survival, stroke, and the presence and duration of anticoagulation were compared between groups.ResultsThe proportion of patients receiving anticoagulation at discharge and at 5 years was not significantly different between patients who underwent LAA exclusion and those who did not; 90% vs 81%, P = 0.156, 48% vs 49%, P = 0.722, respectively. On Kaplan‐Meier analysis there were no significant differences in time free from stroke between cases and controls. Patients discharged on oral anticoagulation (OAC) had significantly lower risk of stroke (HR = 0.19, 95% confidence interval [CI] = 0.06‐0.59, P = 0.004), independent of whether LAA closure was used.ConclusionLAA exclusion did not appear to reduce early or late stroke. Only OAC was associated with a reduction in stroke risk, underscoring the need for continued anticoagulation in high‐risk patients.

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.

AbstractQuantitative cytomegalovirus (CMV) nucleic acid testing (NAT) has been standardized using the World Health Organization (WHO) international calibration standard. A new FDA‐approved WHO‐calibrated assay (CA) was found to be more sensitive than a laboratory‐developed test (LDT). We hypothesized that monitoring therapeutic response using a more sensitive assay may lead to longer antiviral therapy in solid organ and hematopoietic stem cell transplant patients with CMV infection. We reviewed transplant patients with CMV disease retrospectively, and divided them into two groups: those diagnosed and managed based on LDT and those managed using WHO‐CA. Compared to patients monitored by LDT, the time to reach an undetectable viral load was significantly longer in the group monitored by the WHO‐CA. However, a trend toward shorter duration of antiviral treatment was observed (median, 34 vs. 41 d; p = 0.058), with earlier discontinuation of induction antiviral therapy upon reaching undetectable viral load using WHO‐CA (11 vs. 18 d; p = 002). We concluded that despite using a more sensitive CMV NAT, the total duration of antiviral treatment was not significantly prolonged in transplant patients with CMV infection and disease. Relapse rates did not differ between the two groups.