Analytical Performance Evaluation of Three Point-of-Care CBC Analyzers for Management of Clozapine Therapy in Ambulatory Psychiatry Clinics.

BACKGROUND: Clozapine is a first-line therapy and the only FDA-approved drug for patients with treatment-resistant schizophrenia (TRS). However, frequent measurement of absolute neutrophil count (ANC) is required to monitor for potential adverse severe neutropenia from clozapine therapy. We evaluated 3 point-of-care (POC) instruments that perform the complete blood count (CBC) with differential to assess their analytical performance and potential to meet the clinical need for clozapine therapy management. METHODS: A CBC with differential was performed on 104 residual whole blood specimens using 3 CBC analyzers (Sight OLO, PixCell HemoScreen, and Sysmex pocH-100i) to assess analytical precision, linearity, and accuracy vs the ADVIA 2120i and manual differential reference methods. Clinical concordance of ANC between POC devices and manual differential at medical decision points for mild, moderate, or severe neutropenia, and the threshold for clozapine therapy discontinuation (1.0 × 109/L) were determined. RESULTS: For CBC parameters, a CV ≤ 6.4% was observed on the OLO, CV ≤ 6.2% for the HemoScreen, and CV ≤ 5.1% with the pocH-100i. Each device accurately identified ANC with the greatest mean bias ±0.42 × 109/L using the pocH-100i vs manual differential. For results near the medical decision points (ANC <1.5 × 109/L), clinical concordance of ANC results was 55.6% for the OLO, 89.5% for the HemoScreen, and 82.4% for the pocH-100i. CONCLUSIONS: The HemoScreen device demonstrated the best clinical concordance in ANC values at medical decision thresholds for clozapine therapy management.

Monitoring tacrolimus toxicity following Paxlovid administration in a liver transplant patient.

Maintaining therapeutic plasma tacrolimus concentrations is essential for mitigating potential solid organ transplant rejection and preventing toxic adverse side effects. While patients can benefit greatly from tacrolimus therapy, co-administration of drugs such as Paxlovid (nirmatrelvir/ritonavir) place patients at serious risk for drug interactions and harm. Here we present a case of tacrolimus toxicity following Paxlovid administration in a liver transplant patient. Therapeutic drug monitoring was further complicated by a limited upper reportable threshold for tacrolimus testing and highlights the value of validating a higher limit to the clinical reportable range to improve tacrolimus monitoring and meet clinical needs in the setting of drug toxicity.

Current Issues in Blood Gas Analysis.

BACKGROUND: Blood gas analysis constitutes one of the most widely used tests, especially in critical care settings such as intensive care units, emergency departments, and operating rooms. Blood gas results are key for assessing acid-base balance and ventilatory control in critically ill patients. Because blood gas analysis plays a vital role in management of critically ill patients, this testing is frequently conducted at the point-of-care by users with various educational backgrounds across different hospital departments. CONTENT: When performing blood gas analysis, it is important to be aware of the analytical issues that may affect the different components of this testing. With blood gas analysis, differences in test names and method changes over time have led to several controversies that might affect test result interpretations. Hence, being aware of these controversies is important in ensuring appropriateness of result interpretations. Many blood gas testing programs face challenges with maintaining quality assurance. Having practical approaches to method verification, and choosing the right blood gas analyzer type, will go a long way to ensure quality in blood gas analysis. SUMMARY: We review analytical issues and controversies associated with blood gas testing, as well as practical approaches to deciding on a blood gas analyzer and quality assurance.

Activated clotting time in inpatient diagnostic and interventional settings.

Monitoring for the anticoagulant effect of unfractionated (UFH) at the point of care using activated clotting time in real time is vital where risk of thrombosis is high. Although monitoring UFH effect is a routine and important task, changing from one ACT instrument type or technology to another must be preceded by a clinical and statistical evaluation to determine the suitability and repeatability and establish normal and treatable ranges of this newer instrument. In this multi-center prospective evaluation we tested 1236 paired ACT+ samples, and 463 paired ACT-LR samples (1699 total) from enrolled study subjects. Clinical settings included CVOR cardiopulmonary bypass, at the beside in extracorporeal life support (ELS), the Cardiac Catheterization Lab (CCL) during diagnostic studies and percutaneous coronary interventions (PCI), interventional radiology procedures and EP interventions. This study found more consistent clinical performance from the GEM Hemochron 100 as compared to the current clinical model, the Hemochron Signature Elite. The bias of GEM Hemochron 100 for ACT+ and ACT-LR was greatest in the setting of the CVOR where ACT levels were high. ACT-LR measurements by the GEM Hemochron 100 were comparable to the SE when performed in settings of CCL, ECM, EP and ICU. Results obtained for both ACT-LR and ACT+ in all clinical settings in this study using the GEM Hemochron 100 are as accurate and more repeatable as those with the current clinically available Signature Elite.

Comparative Analyses of Three Point-of-Care Urine Drug Test Devices' Performance Characteristics for Use in Ambulatory Clinic Settings.

BACKGROUND: Urine drug testing (UDT) is a standard practice used for monitoring controlled and illicit substances in ambulatory care patients. Point-of-care (POC) UDTs are useful tools that allow for drug identification within minutes, providing rapid and objective diagnostic assistance for clinicians. The objective of this study was to evaluate the performance characteristics of 3 different POC UDT devices compared to reference methods. METHODS: A total of 106 residual urine specimens were collected to evaluate the 3 POC UDT devices: the Profile®-V MEDTOX Scan® drugs of abuse test, Quidel Triage® TOX Drug screen, and Quidel Triage Rapid OXY-BUP-MDMA panel. Device performance was assessed by their ability to identify drug classes/compounds compared to manufacturer and reference method (mass spectrometry) cutoffs. RESULTS: The results from quantitative mass spectrometry showed that 77% (84/106) of the samples were positive for one or more drugs. Each device had variable performance across each drug class. Overall, the specificity of the Profile-V MEDTOX Scan test was 90.1%, while the Quidel Triage TOX Drug Screen and Rapid OXY-BUP-MDMA devices had specificities of 89.0% and 50.0% using their respective manufacturer-stated cutoffs. Overall sensitivity was determined to be 98.6%, 97.0%, and 100% for the Profile-V MEDTOX Scan, Quidel Triage TOX Drug Screen, and Rapid OXY-BUP-MDMA, respectively. CONCLUSIONS: Of the 3 POC UDT devices evaluated, the Profile-V MEDTOX Scan demonstrated the best overall sensitivity and specificity compared to reference methods. False positive and negative results are possible with UDTs, ultimately the best device may depend on patient population and drugs of interest.

Characterization of biotin interference in 21 Vitros 5600 immunoassays and risk mitigation for patient safety at a large academic medical center.

BACKGROUND: Biotin and streptavidin are commonly used reagents in clinical immunoassays. Several cases of biotin interference with immunoassay testing for patients taking biotin supplements have been reported, yet, not all analytes and platforms susceptible to biotin interference have been characterized. The objectives of this study are to characterize biotin interference with 21 immunoassays using the Ortho Clinical Diagnostics Vitros 5600, evaluate a biotin-depletion method, and apply risk mitigation strategies for biotin interference during routine clinical testing at our institution. METHODS: Residual serum without and with increasing concentrations of exogenous biotin were used to evaluate biotin interference with 21 immunoassays using the Vitros 5600. Biotin-depletion was evaluated by comparing measured analyte concentrations in serum with and without exogenous biotin and streptavidin-microparticle pretreatment. Focused education for healthcare professionals about biotin interference was performed in February 2018. Samples with suspected biotin interference were investigated using this biotin-depletion method, and analyte testing by alternate methodology for select samples. RESULTS: Exogenous biotin in serum caused dose-dependent negative biases in 15 immunometric assays, and dose-dependent positive biases in 6 competitive immunoassays. Streptavidin-microparticle pretreatment of serum containing exogenous biotin demonstrated recoveries 100 ±â€¯15% of expected values for all 21 analytes. Physicians identified 21 samples suspicious for biotin interference over 11 months, and streptavidin-microparticle pretreatment verified 11 cases of biotin interference. CONCLUSIONS: Analytical bias caused by biotin interference is dependent on biotin concentration but independent of analyte concentration for immunometric methods using the Vitros 5600, and dependent on both biotin and analyte concentration for competitive immunoassays. Multi-disciplinary education and a lab streptavidin-microparticle pretreatment method help mitigate risk of erroneous results due to biotin interference for patient safety.

Suspected Testosterone-Producing Tumor in a Patient Taking Biotin Supplements.

A perimenopausal woman presented with palpitations, hirsutism, and inability to lose weight. Laboratory tests revealed an unusual endocrine hormonal profile including pituitary hormones (TSH, ACTH, and prolactin) below reference intervals and gonadal (testosterone) and adrenal (cortisol) hormones above reference intervals. Ultimately, after a comprehensive workup including a scheduled surgical procedure, abnormal laboratories were determined due to biotin interference. Biotin (vitamin B7) is a water-soluble vitamin and essential cofactor for the metabolism of fatty acids, glucose, and amino acids. The recommended daily intake of biotin for adults is 30 µg/d. Many over-the-counter products, particularly those marketed for hair, skin, and nail growth, contain biotin 100-fold of recommended daily intake. This case is unique due to the abnormalities observed not only in the well-described TSH "sandwich" immunoassay, but also in tests for gonadal steroids, adrenal, and pituitary hormones. Falsely high as well as falsely low results can be ascribed to biotin. Competitive immunoassays (Fig. 1A)- in this case, tests used initially for serum cortisol and testosterone- can demonstrate falsely high results. Interference falsely lowers the immunometric "sandwich" immunoassay (Fig. 1B)-in this case, TSH. Biotin effect on our patient's endocrine testing led to decidedly abnormal findings, unnecessary medical referrals and diagnostic studies, and comprehensible psychological distress. Interference with one immunoassay, TSH, persisted a full 2 weeks after discontinuation of biotin; indeed, some tests demonstrate sensitivity to lesser quantities of biotin. Improved communication between patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.

Reference intervals and diagnostic ranges for serum free κ and free λ immunoglobulin light chains vary by instrument platform: Implications for classification of patient results in a multi-center study.

BACKGROUND: Serum free light chain (FLC) immunoglobulins are key biomarkers that aid in the diagnosis, prognosis and assessment of treatment response in patients with plasma cell disorders (PCD). Here we investigated the transference of manufacturer's reported κFLC, λFLC and κ to λ FLC reference intervals (RI) and established de novo FLC RI and diagnostic ranges on four instruments at three academic medical centers. In addition, we also compared the classification of patient FLC results using manufacturer's versus established RIs and diagnostic ranges. METHODS: CLSI EP28-A3C protocol was applied to investigate transference and establishment of FLC reference intervals on the cobas (Roche), Immage (Beckman), Optilite and SPA Plus (Binding Site). Serum κ FLC and λ FLC were measured in reference sera (N = 126) with estimation of central 95% RIs and FLC ratio diagnostic range (total range). Frequencies (%) in patient FLC results (N > 380 per institution) classified above, below or within manufacturer's versus established FLC RI were compared. RESULTS: Three of four instrument platforms did not exhibit acceptable transference of manufacturer's reported κ FLC RI. The manufacturer's reported FLC total diagnostic range did not encompass all values observed in reference sera for any of the four platforms evaluated. Established FLC ratio diagnostic ranges reduced the frequency of patient results classified above range for three of four platforms evaluated. CONCLUSIONS: Transference of manufacturer's reported FLC RIs may be inappropriate for select instrument platforms. De novo establishment of FLC RIs specific to instrument platform is highly recommended in order to assure correct patient result classification.

Comparison of Point-of-Care Activated Clotting Time Methods in Different Clinical Settings in a Large Academic Medical Center.

OBJECTIVES: This study is a comparative analysis of measured activated clotting time (ACT) values by use of 5 different point-of-care (POC) ACT methods spanning the range detected during different clinical procedures at our institution. METHODS: We determined the correlation, imprecision, and differences in measured ACT values with use of 4 POC ACT methods compared with a reference ACT method in 41 venous whole blood samples collected from 25 adult patients undergoing interventional procedures. The POC ACT methods evaluated included the i-STAT with kaolin activator in prewarm mode, i-STAT with Celite activator in prewarm and nonprewarm modes, ACTPlus, and HMSPlus, which was designated the reference method. Each venous whole blood patient sample was tested in duplicate on each POC ACT test system (total n = 410 ACT measurements). Analyses of imprecision and differences in measured ACT values were stratified by moderate (100-299 s) and high (≥300 s) ACT ranges. RESULTS: In this study population, measured ACT values ranged from 100-835 s with use of the HMSPlus. All methods demonstrated good correlation (r ≥ 0.95) in ACT values compared to the reference method. Imprecision varied by method with ranges of 1.7%-2.7% CV in the moderate ACT range and 2.5%-4.8% CV in the high ACT range. ACTPlus and i-STAT-Celite-prewarm methods exhibited proportional differences in measured ACT values whereas the i-STAT-Celite-nonprewarm and i-STAT-kaolin-prewarm demonstrated constant differences in measured ACT values compared to HMSPlus. CONCLUSIONS: ACT values correlate well between POC methods. Imprecision and difference profiles vary by method; notably, imprecision exceeds systematic differences in the high ACT range and contributes to intermethod differences that are limitations worthy of consideration when contemplating a change in ACT methods.

Using a simulation model to assess risk of false negative point-of-care urinary human chorionic gonadotropin device results due to high-dose hook interference.

BACKGROUND: It is unclear if the point-of-care (POC) Clinitest hCG device is subject to high-dose hook interference from physiological concentrations of intact human chorionic gonadotropin (hCG), ß-core fragment of hCG (hCGßcf), and hCG free ß-subunit (hCGß) found in urine during pregnancy. We used a simulation model to address this question and related our findings to our institution's pregnant population in order to assess risk for potential false-negative hCG results. METHODS: The expected distribution of days relative to ovulation during routine POC hCG testing was estimated from 182 patients. Clinitest-Clinitek Status hCG device susceptibility to high-dose hook interference from hCG variants and potential risk of false-negative results as it relates to this population were evaluated by testing increasing concentrations of hCG, hCGßcf, hCGß as well as urine simulating physiological hCG, hCGßcf and hCGß concentrations expected during early pregnancy (≤44 days post-ovulation). RESULTS: The Clinitest-Clinitek Status hCG device exhibited high-dose hook interference from hCGßcf alone, but not from hCG, hCGß, or simulated physiological urinary concentrations of combined hCG, hCGßcf and hCGß expected during early pregnancy. The majority of our patient population had urinary hCG testing conducted during early pregnancy. CONCLUSION: The Clinitest-Clinitek Status hCG device is unlikely to exhibit false-negative urinary hCG results due to high-dose hook interference for women in early healthy pregnancy, although additional studies are necessary to determine potential risk in other patient populations. Visual interpretation of POC urinary hCG device results is an important failure mode to consider in risk analyses for erroneous urinary hCG device results.

Utilization of assay performance characteristics to estimate hemoglobin A1c result reliability.

BACKGROUND: Allowable total error (TE(a)) goals for hemoglobin (Hb) A(1c) require minimal assay imprecision and bias and implementation of a robust QC monitoring program. Here, we compare the combined influence on the risk of reporting unreliable results of TE(a) goals, a routine QC practice, and assay performance characteristics of 6 Hb A(1c) instruments across 4 academic medical centers. METHODS: The CLSI protocols EP-5 and EP-9 were applied to investigate Hb A(1c) result imprecision and bias on the Variant II Turbo and Variant II (Bio-Rad), G8 (Tosoh), Capillarys 2 Flex Piercing (Sebia), COBAS Integra 800 (Roche), and DCA Vantage (Siemens). Patient-weighted σ values and the risk of reporting unreliable Hb A(1c) results were determined for each assay at TE(a) specifications of 5%, 6%, and 7%. RESULTS: A large range of patient-weighted σ values spanning 0.5 orders of magnitude at a 6% TE(a) was observed. Although imprecision for all instruments was <3%, bias impacted the majority of the σ changes observed. Estimates for reporting unreliable results varied almost 500-fold based on analytical performance alone. CONCLUSIONS: Considerable differences in the probability of reporting unreliable Hb A(1c) results between different NGSP (formerly the National Glycohemoglobin Standardization Program)-certified platforms were observed. At a 6% TE(a), our study indicates all but the Capillarys 2 Flex Piercing requires that the maximum affordable QC be run. Risk estimates for individual laboratories' Hb A(1c) methods can be used to assess QC practices and residual risk of an unreliable Hb A(1c) result.

Osteoporosis in men.

Osteoporosis in men causes significant morbidity and mortality. Bone health declines gradually, often insidiously; and in light of the advancing aging population poses a serious public health issue that is not well recognized. Studies of the past decade have expanded our understanding of the events within, as well as the regulation of, bone remodeling and provided better insight into the physiology and pathophysiology specific to the adult male skeleton. The clinical measurement of bone mineral density using dual-energy X-ray absorptiometry remains the gold standard for diagnosis of osteoporosis in males; and fracture risk assessment is now recognized as a preferred approach to guide treatment decisions. Utilizing surrogate end-points such as increasing bone mineral density and decreasing concentrations of bone resorption markers, clinical trials have demonstrated efficacy in pharmacological treatment of osteoporosis in the adult male. Unfortunately, few studies have evaluated the anti-fracture benefits in this population. Measurement of bone turnover markers may be an additional tool to monitor therapeutic responsiveness in addition to the measurement of bone mineral density.