Zoonotic Bacterial Infections Triggering Cytokine Storm Syndrome.

Zoonotic infections can result in life-threatening complications that can manifest with hemophagocytic lymphohistiocytosis (HLH)/cytokine storm syndrome (CSS). Bacteria constitute the largest group of zoonotic infection-related HLH cases. The growing list of zoonotic bacterial infections associated with HLH/CSS include Brucella spp., Rickettsia spp., Ehrlichia, Coxiella burnetii, Mycobacterium spp., and Bartonella spp. Patients most commonly present with fever, cytopenias, hepatosplenomegaly, myalgias, and less frequently with rash, jaundice, and lymphadenopathy.

Human ehrlichiosis at a tertiary-care academic medical center: Clinical associations and outcomes of transplant patients and patients with hemophagocytic lymphohistiocytosis.

BACKGROUND: Ehrlichiosis is an acute febrile tick-borne disease which can rarely be a trigger for secondary hemophagocytic lymphohistiocytosis (HLH). METHODS: We reviewed our experience with Ehrlichia infections at a tertiary-care academic medical center. RESULTS: Over 10 years, 157 cases of ehrlichiosis were identified. Ten patients (6.4%) had infection with E. ewingii, 7(4.5%) of whom were transplant patients as compared to 3(1.9%) non-transplant patients (p = .035). Transplant patients were more likely to have leukopenia and elevated creatinine compared to immunocompetent patients; length of hospital stay and early mortality were not different between the two groups. Ten patients met the HLH-2004 diagnosis criteria, which could be an underestimation of HLH occurrence as most patients were not completely evaluated for these criteria. We calculated the H-Score to find the probability of HLH; 25 patients scored high making the occurrence rate of HLH at least 16%. Ehrlichia-induced HLH patients (N = 25) had more anemia, thrombocytopenia, elevated creatinine and AST. Moreover, they had a significantly longer hospital stay (median 9 days) compared to patients without HLH (median 4 days) (p = .006). CONCLUSIONS: Ehrlichia-induced HLH is a potential serious complication with relatively high occurrence rate; patients manifest severe disease with end-organ damage requiring longer hospital stay.

Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial.

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown. Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery. Design, Setting, and Participants: The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application. Main Outcomes and Measures: The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more. Results: Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%). Conclusions and Relevance: Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01006733.

Heartland Virus and Hemophagocytic Lymphohistiocytosis in Immunocompromised Patient, Missouri, USA.

Heartland virus is a suspected tickborne pathogen in the United States. We describe a case of hemophagocytic lymphohistiocytosis, then death, in an immunosuppressed elderly man in Missouri, USA, who was infected with Heartland virus.

Elevated serum ferritin is not specific for hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, syndrome of excessive and ineffective activation of the immune system. The majority of the reported data on HLH is from pediatric patients and lacks specificity. This makes HLH diagnosis challenging especially in adults where HLH is triggered by many conditions and can resemble many disease entities. Elevated ferritin is one of the diagnostic criteria for HLH. We determined the conditions associated with elevated ferritin at our medical center to assess how specific ferritin is for predicting HLH. We retrospectively reviewed all ferritin results >10,000 µg/L in pediatric and adult patients. The most common condition associated with elevated ferritin was hematologic malignancy in adults (25.7%) and HLH in pediatric patients (48.9%). HLH was diagnosed in 14.2% of adults and 48.9% of children with ferritin >10,000 µg/L. Hyperferritinemia occurs in a variety of conditions and is not specific for adult or pediatric HLH. Common causes of elevated ferritin should be considered before entertaining the possibility of HLH, especially in adult patients.

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients: The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. Main Outcomes and Measures: The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Results: Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths. Conclusions and Relevance: Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing. Trial Registration: clinicaltrials.gov Identifier: NCT01006733.

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

Ehrlichia-Induced Hemophagocytic Lymphohistiocytosis: A Case Series and Review of Literature.

Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially fatal syndrome characterized by an uncontrolled hyperinflammatory response. The secondary form of HLH is usually triggered by a causative agent. Ehrlichia chaffeensis is a rare trigger of secondary HLH. We present a case series of five adolescents and adults diagnosed with Ehrlichia-induced HLH and we discuss their clinical and laboratory findings. We also review the literature for similar cases. Between October 2003 and June 2014, we identified 76 cases of HLH in adolescents and adults, 5 of which were induced by Ehrlichia. All 5 patients had fever, cytopenias, hypertriglyceridemia, and high ferritin. Hyperferritinemia was striking with a median admission ferritin of 47,290 µg/L (range: 2,863-85,517). In addition to the positive Ehrlichia PCR testing on peripheral blood of all patients, two patients with neurologic symptoms tested positive for E. chaffeensis in CSF specimens. Early treatment with doxycycline was effective. After a median follow up of 7.3 months, all patients were alive and none had recurrence of HLH. Clinicians should consider E. chaffeensis as a potential trigger for HLH especially in areas with tick activity. Prompt diagnosis and treatment with doxycycline are required for a better outcome.

Cancer-Associated Venous Thromboembolic Disease, Version 1.2015.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by the activation of the mononuclear phagocytic system. The diagnosis of HLH in adults is challenging not only because the majority of the reported data are from pediatric patients, but also because HLH occurs in many disease entities. This study reports the clinical and laboratory findings and prognostic factors of adult HLH in a large cohort managed at a single medical center from 2003 to 2014. Seventy-three patients met the HLH-2004 diagnostic criteria. The median age was 51 years (range, 18-82 years); 41 (56.2%) were male. Patients manifested fever, cytopenias, and elevated ferritin in >85% of cases. Likely causes of HLH were as follows: 30 (41.1%) infections, 21 (28.8%) malignancies, 5 (6.8%) attributed to autoimmune disorders, 1 (1.4%) primary immunodeficiency, 2 (2.7%) post solid organ transplantation, and 13 (17.8%) idiopathic. The median overall survival was 7.67 months. Patients with malignancy-associated HLH had a markedly worse survival compared with patients with non-malignancy-associated HLH (median overall survival 1.13 vs. 46.53 months, respectively; P < 0.0001). In a multivariable analysis, malignancy (hazard ratio = 12.22; 95% CI: 2.53-59.02; P = 0.002) correlated with poor survival. Ferritin >50,000 µg/L correlated with 30-day mortality. Survival after a diagnosis of HLH is dismal, especially among those with malignancy-associated HLH. The development of a registry for adults with HLH would improve our understanding of this syndrome, validate diagnostic criteria, and help develop effective treatment strategies.

Estimation of gestational age-specific reference intervals for coagulation assays in a neonatal intensive care unit using real-world data.

BACKGROUND: Interpretation of coagulation testing in neonates currently relies on reference intervals (RIs) defined from older patient cohorts. Direct RI studies are difficult, but indirect estimation may allow us to infer normative neonatal distributions from routinely collected clinical data. OBJECTIVE: Assess the utility of indirect reference interval methods in estimating coagulation reference intervals in critically ill neonates. METHODS: We analyzed first-in-life coagulation testing results from all patients admitted to a level IV neonatal intensive care unit between January 1, 2018, and January 1, 2024. Results obtained after transfusion of any blood product were excluded. Indirect RIs were estimated across gestational age groups using refineR and compared with currently reported intervals for patients less than 1 year of age. RESULTS: Prothrombin times (PTs) and international normalized ratios (INRs) were available for 1128 neonates, while activated partial thromboplastin times (APTTs) were available for 790 neonates. The indirect RI was 10 to 25 seconds in preterm, 10 to 22 seconds in term, and 10 to 24 seconds in all neonates for PT; 0.7 to 2.1 in preterm, 0.8 to 1.8 in term, and 0.8 to 1.9 in all neonates for INR; and 25 to 68 seconds in preterm, 25 to 58 seconds in term, and 25 to 62 seconds in all neonates for APTT. Compared with our current intervals, the indirect RIs would flag 58% fewer PT, 43% fewer INR, and 17% fewer APTT results as abnormal. CONCLUSION: Indirectly estimated RIs in neonates admitted to intensive care show substantial divergence from current, first-year-of-life RIs, leading to an abundance of abnormal flags. The associations between these flags and provider behavior, transfusion practice, or clinical outcomes are areas of future exploration.

Evaluation of an automated von Willebrand factor glycoprotein IbM activity assay compared with 3 alternative von Willebrand factor activity assays.

Background: To overcome deficiencies of the traditional von Willebrand factor (VWF) ristocetin cofactor activity assay (VWF:RCo), several automated assays for VWF platelet-binding activity have been developed. Information on the performance of these assays and their diagnostic utility remains limited. Objectives: To validate the VWF:glycoprotein IbM assay INNOVANCE VWF Ac and compare it with an automated VWF:RCo assay as well as with an automated assay and a manual VWF:Ab assay and to generate reference ranges and analyze reproducibility of the VWF:glycoprotein IbM assay. Methods: Clinical sites enrolled healthy subjects and patients representing the intended use population; VWF activity assays were performed, and results were analyzed. The performance of the INNOVANCE VWF Ac assay was also compared between the BCS XP System and the CS-2500 and CS-5100 analyzers. Results: The INNOVANCE VWF Ac assay correlated well with the VWF:RCo assay and the automated HemosIL VWF:Ab assay, with Pearson coefficients of >.9 and a predicted bias of ≤5.0 IU/dL at VWF levels of 30 IU/dL and ≤5.8 IU/dL at the levels of 50 IU/dL, but correlation and bias were not as good when compared with the REAADS manual VWF:Ab assay. Reference ranges observed for healthy subjects correlated well with previously published findings. Reproducibility of the INNOVANCE VWF Ac assay on the BCS XP System and the CS analyzers was excellent, as was correlation among devices. Conclusion: The characteristics of the INNOVANCE VWF Ac assay regarding comparability with other VWF activity assays, reference ranges, and precision support the use of this assay for evaluation of patients with concern for von Willebrand disease.

Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial.

BACKGROUND: Current dosing practices for warfarin are empiric and result in the need for frequent dose changes as the international normalized ratio gets too high or too low. As a result, patients are put at increased risk for thromboembolism, bleeding, and premature discontinuation of anticoagulation therapy. Prior research has identified clinical and genetic factors that can alter warfarin dose requirements, but few randomized clinical trials have examined the utility of using clinical and genetic information to improve anticoagulation control or clinical outcomes among a large, diverse group of patients initiating warfarin. METHODS: The COAG trial is a multicenter, double-blind, randomized trial comparing 2 approaches to guiding warfarin therapy initiation: initiation of warfarin therapy based on algorithms using clinical information plus an individual's genotype using genes known to influence warfarin response ("genotype-guided dosing") versus only clinical information ("clinical-guided dosing") (www.clinicaltrials.gov Identifier: NCT00839657). RESULTS: The COAG trial design is described. The study hypothesis is that, among 1,022 enrolled patients, genotype-guided dosing relative to clinical-guided dosing during the initial dosing period will increase the percentage of time that patients spend in the therapeutic international normalized ratio range in the first 4 weeks of therapy. CONCLUSION: The COAG will determine if genetic information provides added benefit above and beyond clinical information alone.

Linear relationship between lymphocyte counts in peripheral blood and buffy coat collected during extracorporeal photopheresis.

BACKGROUND: Extracorporeal photopheresis (ECP) is commonly used to treat patients with graft-versus-host disease (GVHD) and lung transplant rejection (LTR) in our institution. The quantitative relationship between the number of white blood cells treated during ECP and the cell count in peripheral blood is unclear. STUDY DESIGN AND METHODS: Patients with GVHD and LTR receiving ECP with either UVAR XTS or CELLEX (Therakos) were prospectively recruited for this study. A complete cell count with differential was performed on preprocedural peripheral blood and samples from the collected buffy coats. Correlation analysis and linear regression were performed between cell counts in peripheral blood and buffy coat. Collection efficiency was compared between UVAR XTS and CELLEX. RESULTS: In all 52 patients, lymphocyte counts in buffy coat and peripheral blood showed strong correlation (r values were 0.85 and 0.983 for UVAR XTS and CELLEX, respectively; p < 0.001) with slopes of 2 and 5.1 for UVAR XTS and CELLEX, respectively (p < 0.001). The quantitative relationship remained robust in patients stratified by diagnoses. Monocytes also showed consistent correlation and linearity, but not neutrophils or combined white blood cells, red blood cells, or platelets. CELLEX enriched approximately twice as many lymphocytes and monocytes than UVAR XTS per procedure (p < 0.001). CONCLUSION: The preprocedural peripheral lymphocyte count can predict the number of lymphocytes within the buffy coat collected during ECP, which may justify the use of peripheral lymphocyte count as a surrogate for the cell dose treated per procedure. Peripheral monocyte counts may serve as an alternative. CELLEX is more efficient in collecting lymphocytes and monocytes than UVAR XTS under conditions tested.

Venous thromboembolic disease.

Venous thromboembolism (VTE) remains a common and life-threatening complication among patients with cancer. Thromboprophylaxis can be used to prevent the occurrence of VTE in patients with cancer who are considered at high risk for developing this complication. Therefore, it is critical to recognize the various risk factors for VTE in patients with cancer. Risk assessment tools are available to help identify patients for whom discussions regarding the potential benefits and risks of thromboprophylaxis would be appropriate. The NCCN Clinical Practice Guidelines in Oncology for VTE provide recommendations on risk evaluation, diagnosis, prevention, and treatment of VTE in patients with cancer.

Warfarin pharmacogenetics: does more accurate dosing benefit patients?

After a decade of clinical investigation, pharmacogenetic-guided initial dosing of warfarin is at a crossroads. Genotypes for two single nucleotide polymorphisms (SNPs) in the cytochrome P 450 2C9 gene, affecting warfarin metabolism, and one SNP in vitamin K reductase complex 1 gene, affecting warfarin sensitivity, account for approximately 30% of therapeutic warfarin dosing variability in whites and Asians. Incorporating this genetic information, along with patient's age, body size, and other clinical information improves the accuracy of initial warfarin dosing. Currently, there is insufficient evidence to support the clinical benefits and cost effectiveness of routine warfarin pharmacogenetics. Results from ongoing international randomized clinical trials should provide clarity about the place of warfarin pharmacogenetics in personalized medicine.