The role of chitinases has been focused as potential biomarkers in a wide number of inflammatory diseases, in monitoring active disease state, and predicting prognosis and response to therapies. The main chitinases, CHIT1 and YKL-40, are derived from 18 glycosyl hydrolases macrophage activation and play important roles in defense against chitin-containing pathogens and in food processing. Moreover, chitinases may have organ- as well as cell-specific effects in the context of infectious diseases and inflammatory disorders and able to induce tissue remodelling. The CHIT1 measurement is an easy, reproducible, reliable, and cost-effective affordable assay. The clinical use of CHIT1 for the screening of lysosomal storage disorders is quite practical, when proper cut-off values are determined for each laboratory. The potential of CHIT1 and chitinases has not been fully explored yet and future studies will produce many surprising discoveries in the immunology and allergology fields of research. However, since the presence of a null CHIT1 gene in a subpopulation would be responsible of false-negative values, the assay should be completed with the other markers such ACE and, if necessary, by genetic analysis when CHIT1 is unexpected low.

Publicly Available April 24, 2023

Pitfalls in the diagnosis of hematuria

Joris Delanghe, Marijn Speeckaert, Sigurd Delanghe, Matthijs Oyaert

Page range: 1382-1387

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Abstract

Detection of hemoglobin (Hb) and red blood cells in urine (hematuria) is characterized by a large number of pitfalls. Clinicians and laboratory specialists must be aware of these pitfalls since they often lead to medical overconsumption or incorrect diagnosis. Pre-analytical issues (use of vacuum tubes or urine tubes containing preservatives) can affect test results. In routine clinical laboratories, hematuria can be assayed using either chemical (test strips) or particle-counting techniques. In cases of doubtful results, Munchausen syndrome or adulteration of the urine specimen should be excluded. Pigmenturia (caused by the presence of dyes, urinary metabolites such as porphyrins and homogentisic acid, and certain drugs in the urine) can be easily confused with hematuria. The peroxidase activity (test strip) can be positively affected by the presence of non-Hb peroxidases (e.g. myoglobin, semen peroxidases, bacterial, and vegetable peroxidases). Urinary pH, haptoglobin concentration, and urine osmolality may affect specific peroxidase activity. The implementation of expert systems may be helpful in detecting preanalytical and analytical errors in the assessment of hematuria. Correcting for dilution using osmolality, density, or conductivity may be useful for heavily concentrated or diluted urine samples.

Opinion Papers

January 5, 2023

Remote decentralized clinical trials: a new opportunity for laboratory medicine

Federico Pennestrì, Giuseppe Banfi, Rossella Tomaiuolo

Page range: 1388-1394

Abstract

The traditional venue of clinical trials has been hospitals or specialized research units, usually requiring participants to come on-site. Although their contribution to biomedical progress is beyond dispute, they are characterised by two crucial logistical and ultimately scientifical limitations: poor retention and poor generalizability of results, as patients often have problems in concluding the investigation on-site. Remote Decentralised Clinical Trials (RDCTs) take advantage of digital technologies to design trial activities closer to the home of participants, with the aims of minimizing travel to health facilities and the risk of infections, improving the quality of life of participants and caregivers, reducing work absenteeism, including broader cohorts of patients and possibly reducing costs. RDCTs represent a minority of current global research, but the Covid-19 pandemic brought them to the fore. The authors of this paper promote the spread of RDCTs, building on early recommendations from international institutions, and provide some examples of their use and potential benefits in laboratory medicine.

February 17, 2023

Striving for a pragmatic contribution of biomarkers results to lifelong health care

Simona Ferraro, Cristina Cereda, Gianvincenzo Zuccotti, Santica Marcovina, Mario Plebani, Elia Mario Biganzoli

Page range: 1395-1403

Abstract

Background The increased role of preventive medicine in healthcare and the rapid technological advancements, have deeply changed the landscape of laboratory medicine. In particular, increased investments in newborn screening tests and policies have been observed. Aim of this paper is to characterize how laboratory professionals engaged in clinical chemistry or newborn screening, in collaboration with experts in econometric, bioinformatics, and biostatistics may address a pragmatic use of laboratory results in the decision-making process oriented toward improvement of health care outcomes. Content The effectiveness of biomarkers on healthcare depends on several factors such as analytical performance, prevalence of the disease, integration of the test within the diagnostic algorithm, associated costs, and social/economic impact of false positive and false negative results. Cost-effectiveness analysis needs to be performed and reliability achieved, by overcoming analytical pitfalls and by improving interpretative criteria. These are challenging issues common to clinical chemistry and newborn screening tests. Following the experience in clinical chemistry, one of the main issues to be approached in newborn screening tests, is the lack of harmonization of results obtained by different methods and the limited healthcare effectiveness. Summary The focus on prevention is a crucial opportunity for laboratory medicine to change how to approach the effectiveness of biomarkers on healthcare. The consolidation within clinical laboratories of professionals with different technical and methodological expertise coupled with the need to produce and manage large sets of data, require the cooperation of professionals from other disciplines to characterize the impact of the tests on epidemiological outcomes for health care policy making process.

IFCC Paper

Publicly Available February 13, 2023

External quality assessment practices in medical laboratories: an IFCC global survey of member societies

Ivan M. Blasutig, Sarah E. Wheeler, Renze Bais, Pradeep Kumar Dabla, Ji Lin, Armand Perret-Liaudet, Annette Thomas, Kandace A. Cendejas, Jean-Marc Giannoli, Anne Vassault, Egon Amann, Qing H. Meng

Page range: 1404-1410

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Abstract

Objectives Clinical laboratory results are required for critical medical decisions, underscoring the importance of quality results. As part of total quality management, external quality assessment (EQA) is a vital component to ensure laboratory accuracy. The goal of this survey was to evaluate the current status of global laboratory quality systems and assess the need for implementation, expansion, or harmonization of EQA programs (EQAP) for Clinical Chemistry and Laboratory Medicine. Methods The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Global Laboratory Quality (TF-GLQ) conducted a survey of IFCC full and affiliate members (n=110) on laboratory quality practice. A total of 41 (37.3%) countries representing all IFCC regions except North America provided responses about EQA availability and practices. Results All 41 countries perform EQA, 38 reported that their laboratories had EQA policies and procedures, and 39 further act/evaluate unacceptable EQA results. 39 countries indicated they have international and/or national EQAP and 30 use alternative performance assessments. EQA frequency varied among countries. Generally, an EQAP provided the EQA materials (40/41) with four countries indicating that they did not have an EQAP in their country. Conclusions Globally, most laboratories participate in an EQAP and have defined quality procedures for EQA. There remain gaps in EQA material availability and implementation of EQA as a part of a total laboratory quality system. This survey highlights the need for education, training, and harmonization and will guide efforts of the IFCC TF-GLQ in identifying areas for enhancing global laboratory quality practices.

Guidelines and Recommendations

Open Access March 24, 2023

Antibody-mediated interferences affecting cardiac troponin assays: recommendations from the IFCC Committee on Clinical Applications of Cardiac Biomarkers

Ola Hammarsten, Janet V. Warner, Leo Lam, Peter Kavsak, Bertil Lindahl, Kristin M. Aakre, Paul Collinson, Allan S. Jaffe, Amy K. Saenger, Richard Body, Nicholas L. Mills, Torbjørn Omland, Jordi Ordonez-Llanos, Fred S. Apple

Page range: 1411-1419

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Abstract

The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

General Clinical Chemistry and Laboratory Medicine

February 15, 2023

Evaluation of four automated clinical analyzers for the determination of total 25(OH)D in comparison to a certified LC-MS/MS

Julien Favresse, Marco Fangazio, Frédéric Cotton, Fleur Wolff

Page range: 1420-1427

Abstract

Objectives The aim of this study was to compare the results of five methods for the determination of total 25(OH)D. For that purpose, two mass spectrometry and three immunoassay methods were used. Methods A total of 124 serum samples were analyzed on five different methods (i.e., a reference LC-MS/MS, Cascadion, Lumipulse, Roche Elecsys II and Roche Elecsys III). Analytical performance against LC-MS/MS was evaluated and compared to the Milan models 1 (analytical performance based on the clinical outcome using thresholds of 12, 20 and 30 ng/mL) and 2 (analytical performance based on biological variation). Additionally, imprecision studies and accuracy using NIST SRM972a samples were carried out. Results Compared to the reference LC-MS/MS method, the Lumipulse and the Roche Elecsys III assays reached the optimal criterion for bias, while the Cascadion met the desirable one. The Roche Elecsys II was not able to reach the minimal criteria. The proportion of correctly classified patients was higher using the Cascadion (95.2%) compared to the three immunoassays. In addition to its better precision, the Cascadion was not impacted by a high concentration of 3-epi-25(OH)D 3 compared to the three immunoassays. Conclusions Compared to the LC-MS/MS reference method, the Cascadion presented the highest level of concordance at medical decision cut-offs for total 25(OH)D and reached the desirable specification for bias. Moreover, the presence of 3-epi-25(OH)D 3 in enriched samples was only problematic in immunoassay methods, and especially considering Roche Elecsys methods. The release of performant fully automated mass spectrometry assays with high throughput might therefore facilitate the wide scale adoption of LC-MS/MS, even in non-specialized clinical laboratories.

February 21, 2023

Standard −20 °C freezer storage protocols may cause substantial plasma renin cryoactivation

Paul Bonnitcha, Mark Rigdwell, Peter Ward, Douglas Chesher

Page range: 1428-1435

Abstract

Objectives To assess the appropriate preanalytical process for storage of plasma for renin concentration analysis. This study was initiated due to the wide variation in preanalytical handling of samples observed within our network, particularly with respect to freezing for longer term storage. Methods Pooled plasma from patient samples was analysed immediately post separation for renin concentration (n=30, concentration 4.0–204 mIU/L). Aliquots from these samples were frozen in a −20 °C freezer and then analysed, with the renin concentration compared to the respective baseline concentration. Comparisons were also made to: aliquots snap frozen using a dry ice/acetone bath, aliquots stored at room temperature, and aliquots stored at 4 °C. Subsequent experiments investigated the potential sources of cryoactivation observed in these initial studies. Results Substantial and highly variable cryoactivation was observed in samples frozen using a −20 °C freezer, with renin concentration increasing over 300% from baseline in some samples (median 21.3%). This cryoactivation could be prevented by snap freezing samples. Subsequent experiments determined that long term storage in a −20 °C freezer could prevent cryoactivation provided samples were initially frozen rapidly in a −70 °C freezer. Rapid defrosting of samples was not required to prevent cryoactivation. Conclusions Standard −20 °C freezers may not be appropriate for freezing samples for renin analysis. Laboratories should consider snap freezing their samples using a −70 °C freezer or similar to avoid cryoactivation of renin.

Open Access March 6, 2023

Lower accuracy of testosterone, cortisol, and free T4 measurements using automated immunoassays in people undergoing hemodialysis

Heleen I. Jansen, Antonius E. van Herwaarden, Henk J. Huijgen, Marc G. Vervloet, Jacquelien J. Hillebrand, Anita Boelen, Annemieke C. Heijboer

Page range: 1436-1445

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Abstract

Objectives Hormone measurements using automated immunoassays (IAs) can be affected by the sample matrix. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) is less affected by these matrix effects. In clinical laboratories, testosterone, cortisol and, free thyroxine (FT4) are often measured using IAs. Renal failure alters serum composition in blood samples from people undergoing hemodialysis (HDp) and have, therefore, a complex serum constitution compared to healthy controls (HC). The goal of this study was to investigate the accuracy of testosterone, cortisol, and FT4 measurements in samples of HDp and to get more insight in the interfering factors. Methods Thirty serum samples from HDp and HC were collected to measure testosterone, cortisol, and FT4 using a well standardized isotope dilution (ID)-LC-MS/MS method and 5 commercially available automated IAs (Alinity, Atellica, Cobas, Lumipulse, UniCel DXI). Method comparisons between LC-MS/MS and IAs were performed using both HDp and HC samples. Results Average bias from the LC-MS/MS was for testosterone, cortisol, and FT4 immunoassays respectively up to 92, 7–47 and 16–27% more in HDp than in HC samples and was IA dependent. FT4 IA results were falsely decreased in HDp samples, whereas cortisol and testosterone concentrations in females were predominantly falsely increased. Correlation coefficients between LC-MS/MS and IA results were lower in HDp compared to HC samples. Conclusions Several IAs for testosterone (in women), cortisol, and FT4 are less reliable in the altered serum matrix of samples of HDp than in HC. Medical and laboratory specialists should be aware of these pitfalls in this specific population.

Open Access March 2, 2023

Multicenter study to compare the diagnostic performance of CLIA vs. FEIA transglutaminase IgA assays for the diagnosis of celiac disease

Daan A.R. Castelijn, A.H. Leontine Mulder, Pieter van der Pol, Jolien C. Hollander, Tietie Kuiper, Caroline Bijnens, Jan Damoiseaux, Hetty J. Bontkes

Page range: 1446-1454

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Abstract

Objectives Celiac disease (CD) is an immune-mediated enteropathy driven by gluten intake. Presence of tTG-IgA antibodies is important for the diagnosis. However, different tTG-IgA assays are used and test performance may vary. Therefore, a retrospective multicenter study was performed to compare the diagnostic performance of three assays. Methods The fluorescence enzyme-linked immunoassay (FEIA) EliA Celikey IgA (Phadia), the chemiluminescence immunoassays (CLIA) h-tTG IgA QUANTA Flash ® (Inova Diagnostics) and the anti-tTG ChLIA IgA (Euroimmun) were compared. Diagnostic samples from CD cases (95 adults; 65 children) and controls (479 adults; 253 children) were included. Samples were blinded and reanalyzed on all platforms. Results A high quantitative correlation between platforms was found (p<0.0001). Both CLIA were more sensitive (adults 100%; children 100%) compared to the FEIA (adults 88.4%; children 96.6%). Specificity of all assays was high (≥97.6%) with the FEIA having the highest specificity. A cut-off based on receiver operator characteristic analysis (6.5 U/mL) improved the sensitivity of the FEIA (adults 95.8%; children 100%) without affecting specificity. Cut-off values for the CLIA assays did not need further optimization. With the FEIA, 71% of pediatric cases had a tTG-IgA level ≥10× upper limit of normal compared to 91 and 92% with QUANTA Flash and ChLIA, respectively. Conclusions All platforms have high diagnostic accuracy. The CLIA assays are more sensitive compared to the FEIA assay. A lower cut-off for the FEIA improves diagnostic performance, particularly in adult cases that, as demonstrated in this study, present with lower tTG-IgA levels compared to pediatric cases.

March 6, 2023

Imprecision remains to be improved in the measurement of serum cystatin C with heterogeneous systems

Jie Zeng, Li Zhang, Jiangtao Zhang, Weiyan Zhou, Tianjiao Zhang, Jing Wang, Haijian Zhao, Chuanbao Zhang

Page range: 1455-1462

Abstract

Objectives Except for the large bias of some measurement systems for serum cystatin C (CysC) measurements, unacceptable imprecision has been observed for the heterogenous system. This study analyzed the external quality assessment (EQA) results in 2018–2021 to provide an insight into the imprecision of CysC assays. Methods Five EQA samples were sent to participating laboratories every year. Participants were divided into reagent/calibrator-based peer groups, for which the robust mean of each sample and robust coefficient of variation (CV) were calculated by Algorithm A from ISO 13528. Peers with more than 12 participants per year were selected for further analysis. The limit of CV was determined to be 4.85% based on clinical application requirements. The concentration-related effect on CVs was investigated using logarithmic curve fitting; the difference in medians and robust CVs between instrument-based subgroups was also evaluated. Results The total number of participating laboratories increased from 845 to 1,695 in four years and heterogeneous systems remained the mainstream (≥85%). Of 18 peers with ≥12 participants, those using homogeneous systems showed relatively steady and small CVs over four years, with the mean four-year CVs ranging from 3.21 to 3.68%. Some peers using heterogenous systems showed reduced CVs over four years, while 7/15 still had unacceptable CVs in 2021 (5.01–8.34%). Six peers showed larger CVs at the low or high concentrations, and some instrument-based subgroups presented greater imprecision than others. Conclusions More efforts should be made to improve the imprecision of heterogeneous systems for CysC measurement.

February 20, 2023

Analytical validation of the modified Westergren method on the automated erythrocyte sedimentation rate analyzer CUBE 30 touch

Ivana Lapić, Anamarija Rade, Anđela Kraljević, Marija Miloš, Désirée Coen Herak, Lucija Daskijević, Paula Cerovac, Dunja Rogić

Page range: 1463-1469

Abstract

Objectives Analytical validation of automated erythrocyte sedimentation rate (ESR) analyzers is necessary prior to their implementation into routine practice. Our aim was to perform the analytical validation of the modified Westergren method applied on the CUBE 30 touch analyzer (Diesse, Siena, Italy). Methods Validation included determination of within-run and between-run precision following the Clinical and Laboratory Standards Institute EP15-A3 protocol, comparison with the reference Westergren method, sample stability assessment at both room temperature and 4 °C, after 4, 8 and 24-h storage, and checking the extent of hemolysis and lipemia interference. Results Coefficients of variation (CVs) for within-run precision were 5.2% for the normal and 2.6% for the abnormal range, while between-run CVs were 9.4 and 2.2%, respectively. Comparison with the Westergren method (n=191) yielded Spearman’s correlation coefficient of 0.93, no constant nor proportional difference [y=0.4 (95% CI: −1.7–1.0) + 1.06 (95% CI: 1.00–1.14)x] and a non-significant mean absolute bias of −2.6 mm (95% CI: −5.3–0.2). Lower comparability was evidenced with increasing ESR values, with both constant and proportional differences for ESR values between 40 and 80 mm, and above 80 mm. Sample stability was not compromised up to 8-h storage both at room temperature (p=0.054) and 4 °C (p=0.421). Hemolysis did not affect ESR measurement up to 1.0 g/L of free hemoglobin (p=0.089), while lipemia index above 5.0 g/L affects the ESR result (p=0.004). Conclusions This study proved that CUBE 30 touch provides reliable ESR measurement and satisfactory comparability with the reference Westergren methods, with minor variation related to methodological differences.

Reference Values and Biological Variations

Open Access February 22, 2023

Systematic review and meta-analysis of within-subject and between-subject biological variation data of coagulation and fibrinolytic measurands

Martine J. Hollestelle, Ann Helen Kristoffersen, René N. Idema, Piet Meijer, Sverre Sandberg, Moniek P.M. de Maat, Aasne K. Aarsand

Page range: 1470-1480

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Abstract

Objectives The diagnosis and monitoring of bleeding and thrombotic disorders depend on correct haemostatic measurements. The availability of high-quality biological variation (BV) data is important in this context. Many studies have reported BV data for these measurands, but results are varied. The present study aims to deliver global within-subject (CV I ) and between-subject (CV G ) BV estimates for haemostasis measurands by meta-analyses of eligible studies, by assessment with the Biological Variation Data Critical Appraisal Checklist (BIVAC). Methods Relevant BV studies were graded by the BIVAC. Weighted estimates for CV I and CV G were obtained via meta-analysis of the BV data derived from BIVAC-compliant studies (graded A–C; whereby A represents optimal study design) performed in healthy adults. Results In 26 studies BV data were reported for 35 haemostasis measurands. For 9 measurands, only one eligible publication was identified and meta-analysis could not be performed. 74% of the publications were graded as BIVAC C. The CV I and CV G varied extensively between the haemostasis measurands. The highest estimates were observed for PAI-1 antigen (CV I 48.6%; CV G 59.8%) and activity (CV I 34.9%; CV G 90.2%), while the lowest were observed for activated protein C resistance ratio (CV I 1.5%; CV G 4.5%). Conclusions This study provides updated BV estimates of CV I and CV G with 95% confidence intervals for a wide range of haemostasis measurands. These estimates can be used to form the basis for analytical performance specifications for haemostasis tests used in the diagnostic work-up required in bleeding- and thrombosis events and for risk assessment.

February 17, 2023

Biological variation estimates for spot urine analytes and analyte/creatinine ratios in 33 healthy subjects

Gizem Yılmaz Çalık, Mehmet Şeneş

Page range: 1481-1489

Abstract

Objectives Urine samples are frequently used in the clinical practice. In our study, we aimed to calculate the biological variations (BV) of analytes and analyte/creatinine ratios measured in spot urine. Methods Second-morning spot urine samples were collected from 33 (16 female, 17 male) healthy volunteers once weekly for 10 weeks and analyzed in the Roche Cobas 6,000 instrument. Statistical analyzes were performed using BioVar, an online BV calculation software. The data were evaluated in terms of normality, outliers, steady state, homogeneity of the data, and BV values were obtained by analysis of variance (ANOVA). A strict protocol was established for within-subject (CV I ) and between-subject (CV G ) estimates for both genders. Results There was a significant difference between female/male CV I estimates of all analytes except potassium, calcium and magnesium. No difference was found in CV G estimates. When the analytes that had a significant difference in CV I estimates in spot urine analytes were compared to creatinine, it was observed that the significant difference between the genders disappeared. There was no significant difference between female/male CV I and CV G estimates in all spot urine analyte/creatinine ratios. Conclusions Since the CV I estimates of analyte/creatinine ratios are lower, it would be more reasonable to use them in result reporting. Reference ranges should be used with caution, since II values of almost all parameters are between 0.6 and 1.4. The CV I detection power of our study is 1, which is the highest value.

Open Access March 2, 2023

Short-term biological variation of plasma uracil in a Caucasian healthy population

Anne Winther-Larsen, Anne Tranberg Madsen, Peter H. Nissen, Elke Hoffmann-Lücke, Eva Greibe

Page range: 1490-1496

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Abstract

Objectives Plasma uracil is a new biomarker to assess the activity of dihydropyrimidine dehydrogenase before cancer treatment with fluoropyrimidine drugs. Knowledge on the biological variation of plasma uracil is important to assess the applicability of plasma uracil as a biomarker of drug tolerance and efficacy. Methods A total of 33 apparently healthy individuals were submitted to sequential blood draws for three days. On the second day, blood draws were performed every third hour for 12 h. Plasma uracil was quantified by LC-MS/MS. The within-subject (CV I ) and between-subject (CV G ) biological variation estimates were calculated using linear mixed-effects models. Results The overall median value of plasma uracil was 10.6 ng/mL (range 5.6–23.1 ng/mL). The CV I and CV G were 13.5 and 22.1%, respectively. Plasma uracil remained stable during the day, and there was no day-to-day variation observed. No differences in biological variation components were found between sex and no correlation to age was found. Four samples were calculated to be required to estimate the homeostatic set-point ±15% with 95% confidence. Conclusions Plasma uracil is subject to tight homeostatic regulation without semidiurnal and day-to-day variation, however between-subject variation exists. This emphasizes plasma uracil as a well-suited biomarker for evaluation of dihydropyrimidine dehydrogenase activity, but four samples are required to establish the homeostatic set-point in a patient.

Cardiovascular Diseases

Open Access February 24, 2023

Elevated Hemolysis Index is associated with higher risk of cardiovascular diseases

Charlotte Gils, Dennis Lund Hansen, Mads Nybo, Henrik Frederiksen

Page range: 1497-1505

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Abstract

Objectives In vivo hemolysis is associated with thromboembolism. Although an increased Hemolysis Index (HI) can be due to in vitro as well as in vivo hemolysis, both reflects a more fragile erythrocyte population. We therefore hypothesized that HI above upper reference limit would be associated with an increased risk of cardiovascular disease (CVD). Methods We identified persons with two elevated HI (HI + ) from blood samples analyzed at a university hospital laboratory from 2012 to 2017. We compared their risk of CVD with the risk in matched comparators with normal HI and from the general population. HI + persons and comparators were followed from start date (date of the second elevated HI) until the first of the main outcome: CVD, emigration, death, or end of observation time on December 31, 2018. Results In 43,102 unique HI + persons, the risk of developing CVD was 40% higher compared with the general population and 13% higher compared with the matched blood sample cohort. HI + was associated with a significantly increased cumulative incidence of both arterial and venous CVD compared with the matched blood sample cohort and the general population (respectively 47 and 14% for arterial CVD; 78 and 24% for venous CVD). Moreover, overall mortality risk was significantly higher in patients with HI + than in the two comparator groups. Conclusions Elevated HI is associated with increased risk of arterial and venous CVD and with increased mortality. Our findings imply that HI may contribute as a CVD risk biomarker.

Infectious Diseases

Publicly Available March 8, 2023

Clinical assessment of SNIBE Maglumi SARS-CoV-2 antigen fully-automated chemiluminescent immunoassay

Laura Pighi, Brandon M. Henry, Simone De Nitto, Gianluca Gianfilippi, Gian Luca Salvagno, Mario Plebani, Giuseppe Lippi

Page range: 1506-1510

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Abstract

Objectives Given that SARS-CoV-2 antigen tests will represent a pillar for supporting or surrogating molecular testing in the endemic period, we report here the clinical performance of the new SNIBE Maglumi SARS-CoV-2 antigen fully-automated chemiluminescent immunoassay (MAG-CLIA SARS-CoV-2 Ag). Methods The study population consisted of 181 subjects (mean age 61 ± 21 years; 92 females) undergoing coronavirus disease 2019 (COVID-19) testing at the local diagnostic facility, from December 2022 to February 2023. Routine diagnostic practice involved the collection of a double nostril nasopharyngeal swab, analyzed in duplicate with SARS-CoV-2 antigen (MAG-CLIA SARS-CoV-2 Ag) and molecular (Altona Diagnostics RealStar SARS-CoV-2 RT-PCR Kit) tests. Results A significant Spearman’s correlation was found between MAG-CLIA SARS-CoV-2 Ag and mean Ct values of SARS-CoV-2 E and S genes (r=−0.95; p<0.001). In all nasopharyngeal samples, the area under the curve (AUC) of MAG-CLIA SARS-CoV-2 Ag was 0.86 (95% CI, 0.81–0.90), with 0.71 sensitivity and 1.00 specificity at 7 ng/L cut-off, increasing to 0.98 (95% CI, 0.96–1.00) AUC and 0.96 sensitivity (with 0.97 specificity) in high viral load samples. When SARS-CoV-2 N protein concentration was replaced with raw instrumental readings (i.e., relative light units [RLU]), the AUC in all samples increased to 0.94. A RLU value of 945 was associated with 88.4% accuracy, 0.85 sensitivity, 0.95 specificity, 0.77 negative predictive value (NPV) and 0.97 positive predictive value (PPV), respectively. Conclusions We found satisfactory analytical performance of MAG-CLIA SARS-CoV-2 Ag, which could be used as surrogate of molecular testing for identifying high viral load samples. Broadening the reportable range of values may generate even better performance.

Publicly Available February 20, 2023

Pre-analytical considerations in the development of a prototype SARS-CoV-2 antigen ARCHITECT automated immunoassay

Philip M. Hemken, Eitan Israeli, Russell Taylor, Chris Jacobson, Maria Datwyler, Rene Geissler, Abbas Hadji, Nicolette Jeanblanc, Kinnari Pandya, Marilee Marcinkus, Ryan Piktel, M. Felicia Bogdan, Mary Rodgers, Mark Anderson, Robert Ziemann, Bryan C. Tieman, David Hawksworth, Jeffrey Moore, Kathy S. Otis, Christopher C. Marohnic, Josie Corby, Bailin Tu, Zhihong Lin, Alak Kar, James Hartnett, Carolyn Strobel, Svetoslava Gregory, Tracey Rae, A. Scott Muerhoff, Susan Brophy, John R. Hackett, David Daghfal, Matthew L. Faron, Amorina Cruz, Phaedre Mohr, Lori Sokoll, Gerard J. Davis

Page range: 1511-1517

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Abstract

Objectives To evaluate pre-analytical challenges related to high-volume central laboratory SARS-CoV-2 antigen testing with a prototype qualitative SARS-CoV-2 antigen immunoassay run on the automated Abbott ARCHITECT instrument. Methods Contrived positive and negative specimens and de-identified nasal and nasopharyngeal specimens in transport media were used to evaluate specimen and reagent on-board stability, assay analytical performance and interference, and clinical performance. Results TCID50/mL values were similar for specimens in various transport media. Inactivated positive clinical specimens and viral lysate (USA-WA1/2020) were positive on the prototype immunoassay. Within-laboratory imprecision was ≤0.10 SD (<1.00 S/C) with a ≤10% CV (≥1.00 S/C). Assay reagents were stable on board the instrument for 14 days. No high-dose hook effect was observed with a SARS-CoV-2 stock of Ct 13.0 (RLU>1.0 × 10 6 ). No interference was observed from mucin, whole blood, 12 drugs, and more than 20 cross-reactants. While specimen stability was limited at room temperature for specimens with or without viral inactivation, a single freeze/thaw cycle or long-term storage (>30 days) at −20 °C did not adversely impact specimen stability or assay performance. Specificity of the prototype SARS-CoV-2 antigen immunoassay was ≥98.5% and sensitivity was ≥89.5% across two ARCHITECT instruments. Assay sensitivity was inversely correlated with Ct and was similar to that reported for the Roche Elecsys ® SARS-CoV-2 Ag immunoassay. Conclusions The prototype SARS-CoV-2 antigen ARCHITECT immunoassay is sensitive and specific for detection of SARS-CoV-2 in nasal and nasopharyngeal specimens. Endogenous proteases in mucus may degrade the target antigen, which limits specimen storage and transport times and complicates assay workflow.

Open Access March 27, 2023

SARS CoV-2 spike protein-guided exosome isolation facilitates detection of potential miRNA biomarkers in COVID-19 infections

Selena Mimmi, Anna Maria Zimbo, Salvatore Rotundo, Erika Cione, Nancy Nisticò, Annamaria Aloisio, Domenico Maisano, Anna Maria Tolomeo, Vincenzo Dattilo, Rosaria Lionello, Antonella Fioravanti, Antonio Di Loria, Angela Quirino, Nadia Marascio, Alessandro Russo, Enrico Maria Trecarichi, Giovanni Matera, Ileana Quinto, Carlo Torti, Enrico Iaccino

Page range: 1518-1524

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Abstract

Objectives Nearly three years into the pandemic, SARS-CoV-2 infections are occurring in vaccinated and naturally infected populations. While humoral and cellular responses in COVID-19 are being characterized, novel immune biomarkers also being identified. Recently, an increase in angiotensin-converting enzyme 2 expressing (aka, ACE2 positive) circulating exosomes (ExoACE2) were identified in the plasma of COVID-19 patients (El-Shennawy et al.). In this pilot study, we describe a method to characterize the exosome-associated microRNA (exo-miRNA) signature in ACE2-positive and ACE2-negative exosomal populations (non-ExoACE2). Methods We performed a sorting protocol using the recombinant biotin-conjugated SARS CoV-2 spike protein containing the receptor binding domain (RBD) on plasma samples from six patients. Following purification, exo-miRNA were characterized for ACE2-positive and ACE2-negative exosome subpopulations by RT-PCR. Results We identified differential expression of several miRNA. Specifically let-7g-5p and hsa-miR-4454+miR-7975 were upregulated, while hsa-miR-208a-3p and has-miR-323-3p were downregulated in ExoACE2 vs. non-ExoACE2. Conclusions The SARS CoV-2 spike-protein guided exosome isolation permits isolation of ExoACE2 exosomes. Such purification facilitates detailed characterization of potential biomarkers (e.g. exo-miRNA) for COVID-19 patients. This method could be used for future studies to further the understanding mechanisms of host response against SARS CoV-2.

Open Access February 28, 2023

Monocyte distribution width alterations and cytokine storm are modulated by circulating histones

Daniela Ligi, Bruna Lo Sasso, Chiara Della Franca, Rosaria Vincenza Giglio, Luisa Agnello, Marcello Ciaccio, Ferdinando Mannello

Page range: 1525-1535

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Abstract

Objectives Extracellular histone levels are associated with the severity of many human pathologies, including sepsis and COVID-19. This study aimed to investigate the role of extracellular histones on monocyte distribution width (MDW), and their effect on the release of cytokines by blood cells. Methods Peripheral venous blood was collected from healthy subjects and treated with different doses of a histone mixture (range 0–200 μg/mL) to analyze MDW modifications up-to 3 h and digital microscopy of blood smears. Plasma obtained after 3 h of histone treatment were assayed to evaluate a panel of 24 inflammatory cytokines. Results MDW values significantly increased in a time- and dose-dependent manner. These findings are associated with the histone-induced modifications of cell volume, cytoplasmic granularity, vacuolization, and nuclear structure of monocytes, promoting their heterogeneity without affecting their count. After 3 h of treatment almost all cytokines significantly increased in a dose-dependent manner. The most relevant response was shown by the significantly increased G-CSF levels, and by the increase of IL-1β, IL-6, MIP-1β, and IL-8 at the histone doses of 50, 100, and 200 µg/mL. VEGF, IP-10, GM-CSF, TNF-α, Eotaxin, and IL-2 were also up-regulated, and a lower but significant increase was observed for IL-15, IL-5, IL-17, bFGF, IL-10, IFN-γ, MCP-1, and IL-9. Conclusions Circulating histones critically induce functional alterations of monocytes mirrored by MDW, monocyte anisocytosis, and hyperinflammation/cytokine storm in sepsis and COVID-19. MDW and circulating histones may be useful tools to predict higher risks of worst outcomes.

Letters to the Editor

March 6, 2023

Letter to the Editor regarding the article by Wayne J. Dimech et al. Time to address quality control processes applied to antibody testing for infectious diseases. Clin Chem Lab Med 2023; 61(2):205–212

Tony Badrick

Page range: e135-e136

March 6, 2023

Response to Tony Badrick regarding “Letter to the Editor regarding the article by Wayne J. Dimech et al. Time to address quality control processes applied to antibody testing for infectious diseases. Clin Chem Lab Med 2023; 61(2):205–212 by”

Wayne J. Dimech, Giuseppe A. Vincini, Mario Plebani, Giuseppe Lippi, James H. Nichols, Oswald Sonntag

Page range: e137-e139

February 3, 2023

Monocyte distribution width (MDW) as a reliable biomarker for urosepsis

Luisa Agnello, Anna Maria Ciaccio, Bruna Lo Sasso, Matteo Vidali, Rosaria Vincenza Giglio, Caterina Maria Gambino, Giulia Bivona, Davide Baiamonte, Nicola Pavan, Alchiede Simonato, Marcello Ciaccio

Page range: e140-e142

March 7, 2023

A consistency analysis of common biochemical tests in arterial blood and venous blood of critically ill patients

Nannan Han, Ruhui Pan, Xuejun Zhang, Meimei Wu, Yanmin Chen, Wenge Yu, Xinyao Li, Hongxiang Xie

Page range: e143-e147

February 28, 2023

Test results comparison: is the S-Monovette^® Lithium-Heparin Gel+ a suitable replacement for the S-Monovette^® Lithium-Heparin Gel on Alinity Abbott^®?

Sqalli Ghali, Cavalier Etienne, Onkelinx Bérénice, Gadisseur Romy

Page range: e148-e151

March 2, 2023

Analytical performance of Abbott’s ARCHITECT and Alinity TSH-receptor antibody (TRAb) assays

Hani Choksi, Sheng Han Li, Maria Bhandari, Pow Lee Cheng, Xiao Yan Wang, Vathany Kulasingam

Page range: e152-e155

Open Access February 24, 2023

Cis-AB showing discrepant results across different automated and manual methods: a case report and review of the literature

Eunju Shin, Hanah Kim, Mina Hur, Hyunkyung Lee, In-Sook Sohn, Kyoung Un Park, Dong Hee Seo

Page range: e156-e159

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February 3, 2023

A graphical tool to investigate method validation

Tony Badrick, Peter Hickman, Greg Ward

Page range: e160-e162

February 20, 2023

Live lab-monitor; a customizable HTML-based and systems independent, real-time laboratory overview screen

Marije van der Schaar, Jan van Loon, Ruben Moritz, Huub H. van Rossum

Page range: e163-e164

Congress Abstracts

Publicly Available June 1, 2023

61st National Congress of the Hungarian Society of Laboratory Medicine

Semmelweis University, 8 – 10 June 2023, Budapest, Hungary

Page range: eA57-eA114

Download PDF

Publicly Available June 1, 2023

9th Annual Meeting of the Austrian Society for Laboratory Medicine and Clinical Chemistry (ÖGLMKC)

Salzburg, Austria, 4^th – 7^th July, 2023

Page range: eA115-eA131

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About this journal

Objective
Clinical Chemistry and Laboratory Medicine (CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. It is focused on basic and applied research and cutting-edge clinical laboratory medicine. CCLM is one of the leading journals in the field, with an impact factor over 8. All contributions submitted for publication in CCLM are single-blind peer reviewed by at least two experts in the field. CCLM is led by a multi-institutional editorial board. It is issued monthly, both in print and electronically. Letters to the Editor and Congress Abstracts are published online only.

Please submit your manuscript here

Topics

clinical biochemistry
clinical genomics and molecular biology
clinical haematology and coagulation
clinical immunology and autoimmunity
clinical microbiology
drug monitoring and analysis
evaluation of diagnostic biomarkers
disease-oriented topics (cardiovascular disease, cancer diagnostics, diabetes)
new reagents, instrumentation and technologies
new methodologies
reference materials and methods
reference values and decision limits
quality and safety in laboratory medicine
translational laboratory medicine
clinical metrology

Article formats
Research Articles, Reviews, Mini Reviews and Opinion Papers on all aspects of clinical chemistry and laboratory medicine, Guidelines and Recommendations, Point/Counterpoint Articles, Letters to the Editor, Editorials

For EFLM Academy Members

To take advantage of all the opportunities offered to members of the EFLM Academy, please access your personal area in the EFLM Academy at the link https://academy.eflm.eu/secretariat/login (if you do not remember your login details, you can use the option FORGOT PASSWORD). Click on the section “International Journals” on the left-hand side where you find CCLM as the first listed journal.

Volume 61 Issue 8

Issue of Clinical Chemistry and Laboratory Medicine (CCLM)

Frontmatter

Addressing standardized definitions of post-COVID and long-COVID

The chitinases as biomarkers in immune-mediate diseases

Abstract

Pitfalls in the diagnosis of hematuria

Abstract

Remote decentralized clinical trials: a new opportunity for laboratory medicine

Abstract

Striving for a pragmatic contribution of biomarkers results to lifelong health care

Abstract

External quality assessment practices in medical laboratories: an IFCC global survey of member societies

Abstract

Antibody-mediated interferences affecting cardiac troponin assays: recommendations from the IFCC Committee on Clinical Applications of Cardiac Biomarkers

Abstract

Evaluation of four automated clinical analyzers for the determination of total 25(OH)D in comparison to a certified LC-MS/MS

Abstract

Standard −20 °C freezer storage protocols may cause substantial plasma renin cryoactivation

Abstract

Lower accuracy of testosterone, cortisol, and free T4 measurements using automated immunoassays in people undergoing hemodialysis

Abstract

Multicenter study to compare the diagnostic performance of CLIA vs. FEIA transglutaminase IgA assays for the diagnosis of celiac disease

Abstract

Imprecision remains to be improved in the measurement of serum cystatin C with heterogeneous systems

Abstract

Analytical validation of the modified Westergren method on the automated erythrocyte sedimentation rate analyzer CUBE 30 touch

Abstract

Systematic review and meta-analysis of within-subject and between-subject biological variation data of coagulation and fibrinolytic measurands

Abstract

Biological variation estimates for spot urine analytes and analyte/creatinine ratios in 33 healthy subjects

Abstract

Short-term biological variation of plasma uracil in a Caucasian healthy population

Abstract

Elevated Hemolysis Index is associated with higher risk of cardiovascular diseases

Abstract

Clinical assessment of SNIBE Maglumi SARS-CoV-2 antigen fully-automated chemiluminescent immunoassay

Abstract

Pre-analytical considerations in the development of a prototype SARS-CoV-2 antigen ARCHITECT automated immunoassay

Abstract

SARS CoV-2 spike protein-guided exosome isolation facilitates detection of potential miRNA biomarkers in COVID-19 infections

Abstract

Monocyte distribution width alterations and cytokine storm are modulated by circulating histones

Abstract

Letter to the Editor regarding the article by Wayne J. Dimech et al. Time to address quality control processes applied to antibody testing for infectious diseases. Clin Chem Lab Med 2023; 61(2):205–212

Response to Tony Badrick regarding “Letter to the Editor regarding the article by Wayne J. Dimech et al. Time to address quality control processes applied to antibody testing for infectious diseases. Clin Chem Lab Med 2023; 61(2):205–212 by”

Monocyte distribution width (MDW) as a reliable biomarker for urosepsis

A consistency analysis of common biochemical tests in arterial blood and venous blood of critically ill patients

Test results comparison: is the S-Monovette® Lithium-Heparin Gel+ a suitable replacement for the S-Monovette® Lithium-Heparin Gel on Alinity Abbott®?

Analytical performance of Abbott’s ARCHITECT and Alinity TSH-receptor antibody (TRAb) assays

Cis-AB showing discrepant results across different automated and manual methods: a case report and review of the literature

A graphical tool to investigate method validation

Live lab-monitor; a customizable HTML-based and systems independent, real-time laboratory overview screen

61st National Congress of the Hungarian Society of Laboratory Medicine

Semmelweis University, 8 – 10 June 2023, Budapest, Hungary

9th Annual Meeting of the Austrian Society for Laboratory Medicine and Clinical Chemistry (ÖGLMKC)

Salzburg, Austria, 4th – 7th July, 2023

Test results comparison: is the S-Monovette^® Lithium-Heparin Gel+ a suitable replacement for the S-Monovette^® Lithium-Heparin Gel on Alinity Abbott^®?

Salzburg, Austria, 4^th – 7^th July, 2023