Central role of laboratory medicine in public health and patient care.

Clinical laboratories play a vital role in the healthcare system. Objective medical data provided by clinical laboratories supports approximately 60-70% of clinical decisions, however, evidence supporting this claim is poorly documented and laboratories still lack visibility, despite their indisputable impact on patient care and public health. The International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Outcome Studies in Laboratory Medicine (TF-OSLM) was recently developed to support directed research evaluating the role of laboratory medicine on clinical outcomes. Establishing and documenting this evidence is key to enhance visibility of the field in the eye of the public and other healthcare professionals together with optimizing patient outcomes and health care system operations. In this review, we discuss four areas that exemplify the contribution of laboratory medicine directly to patient care. This includes high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptides (NT-proBNP/BNP) for the diagnosis and prognosis of myocardial infarction and heart failure, respectively, and procalcitonin for the management of sepsis and antibiotic stewardship. Emerging markers of traumatic brain injury and the role of laboratory medicine in the fight against the COVID-19 pandemic are discussed along with an introduction to plans of IFCC TF-OSLM.

Systematic Review of Diagnostic Accuracy of DiaSorin Liaison SARS-CoV-2 Antigen Immunoassay

Background Quantification of SARS-CoV-2 antigens by means of rapid, high-throughput and fully-automated techniques has been proposed as a feasible alternative to overcome the current shortage of resources for routine molecular diagnostics. To this end, we provide here a systematic review of diagnostic accuracy of DiaSorin Liaison SARS-CoV-2 antigen immunoassay. Methods An electronic search was conduced in Medline and Scopus, with no language or date restrictions (up to January 20, 2022), for identifying all published studies articles in which the diagnostic performance of the DiaSorin Liaison SARS-CoV-2 antigen immunoassay was compared with molecular diagnostic techniques. Results The electronic search identified a final number of 11 studies, totalling 4449 oro- and naso-pharyngeal specimens. The pooled diagnostic sensitivity, specificity and area under the curve (AUC) of the Liaison SARS-CoV-2 antigen immunoassay in all samples were 0.51 (95%CI, 0.49-0.54), 1.00 (95%CI, 1.00-1.00) and 0.994 (95%CI, 0.990-0.998), respectively, whilst the overall concordance with molecular diagnostics was 82.1%. The pooled diagnostic sensitivity, specificity and AUC of the Liaison SARS-CoV-2 antigen immunoassay in specimens with high viral load (i.e., cycle threshold values <25-30) were 0.79 (95%CI, 0.75-0.82), 1.00 (95%CI, 0.99-1.00) and 0.911 (95%CI, 0.879-0.943), respectively, whilst the overall concordance with molecular diagnostics in such samples increased to 94.2%. Conclusion The results of this systematic literature review suggest that there is sufficient accuracy of the DiaSorin Liaison SARS-CoV-2 antigen immunoassay in samples with high viral loads that would enable its reliable usage for identifying superspreaders, who are responsible for the vast majority of transmission events.

Fujirebio Lumipulse SARS-CoV-2 antigen immunoassay: pooled analysis of diagnostic accuracy.

We provide here a pooled analysis of accuracy of Fujirebio Lumipulse SARS-CoV-2 Antigen chemiluminescent immunoassay for diagnosing acute SARS-CoV-2 infections. An electronic search was conducted in Scopus and Medline with the keywords "Lumipulse" AND "antigen" AND "SARS-CoV-2" or "COVID-19", up to January 21, 2022, for identifying clinical investigations (minimum sample size ≥100) where diagnostic accuracy of Lumipulse G SARS-CoV-2 Ag was tested against reference molecular techniques. All studies which allowed to construct a 2 × 2 table were included in a pooled analysis. A final number of 21 studies, totalling 17,648 nasopharyngeal and 8538 saliva specimens, were finally included. The pooled diagnostic sensitivity and specificity in nasopharyngeal swabs were 0.80 (95%CI, 0.78-0.81) and 0.98 (95%CI, 0.97-0.98), respectively, whilst the area under the curve and agreement were 0.980 (95%CI, 0.973-0.986) and 94.9%, respectively. In the twelve studies which used the fixed 1.34 pg/mL currently recommended manufacturer's threshold, the diagnostic accuracy remained unvaried. In saliva samples, the pooled diagnostic sensitivity and specificity were 0.75 (95%CI, 0.71-0.75) and 1.00 (95%CI, 0.99-1.00), respectively, whilst the area under the curve and were 0.976 (95%CI, 0.969-0.984) and 98.4%, respectively. In the five studies which used the fixed 0.67 pg/mL currently recommended manufacturer's threshold, the diagnostic accuracy remained unvaried. In conclusion, Lumipulse G SARS-CoV-2 Ag assay demonstrates good diagnostic sensitivity and specificity, thus representing a valuable complementary and integrative option to molecular testing for SARS-CoV-2 in the current pandemic.

Diagnostic performance of the fully automated Roche Elecsys SARS-CoV-2 antigen electrochemiluminescence immunoassay: a pooled analysis.

OBJECTIVES: Among the diagnostic tests that have recently become commercially available for diagnosing coronavirus disease 2019 (COVID-19), the fully-automated Roche Elecsys severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen electrochemiluminescence immunoassay (ECLIA) is one of the most widespread for its adaptability within a system of laboratory automation, rapidity and high-throughput. This article is aimed to provide the results of the first pooled analysis of its accuracy for diagnosing SARS-CoV-2 infections. CONTENT: We carried out an electronic search in Scopus and Medline, without language or date restrictions (i.e., up to January 18, 2022), to identify articles where the diagnostic performance of Roche Elecsys SARS-CoV-2 antigen ECLIA was compared with that of reference molecular diagnostic techniques. SUMMARY: Overall, 11 studies were identified, 10 of which (n=6,095 swabs) provided necessary data for inclusion in a pooled analysis. The pooled diagnostic sensitivity, specificity and area under the curve (AUC) in nasopharyngeal samples were 0.68 (95%CI, 0.66-0.70), 0.99 (95%CI, 0.99-0.99) and 0.958 (95%CI, 0.936-0.980), respectively. The cumulative observed agreement with reference molecular assays was 89.5% and the kappa statistic was 0.735 (95%CI, 0.716-0.754). The pooled diagnostic sensitivity in samples with high viral load (i.e., cycle threshold values <28-30) was 0.95 (95%CI, 0.92-0.97). OUTLOOK: The results of this pooled analysis confirm that the fully-automated Roche Elecsys SARS-CoV-2 antigen ECLIA has high diagnostic specificity and optimal diagnostic sensitivity for identifying nasopharyngeal samples with higher viral load, thus making it a reliable technique for mass screening and for supporting strategies based on shorten isolation and/or quarantine.

Commercial immunoassays for detection of anti-SARS-CoV-2 spike and RBD antibodies: urgent call for validation against new and highly mutated variants.

Measuring the level of protection conferred by anti-SARS-CoV-2 (trimeric) spike or RBD (receptor binding domain) antibodies (especially total and IgG) is a suitable and reliable approach for predicting biological protection against the risk of infection and severe coronavirus disease 2019 (COVID-19) illness. Nonetheless, SARS-CoV-2 has undergone a broad process of recombination since the identification of the prototype lineage in 2019, introducing a huge number of mutations in its genome and generating a vast array of variants of interest (VoI) and concern (VoC). Many of such variants developed several mutations in spike protein and RBD, with the new Omicron (B.1.1.529) clade displaying over 30 changes, 15 of which concentrated in the RBD. Besides their impact on virus biology, as well as on the risk of detection failure with some molecular techniques (i.e., S gene dropout), recent evidence suggests that these mutations may also jeopardize the reliability of currently available commercial immunoassays for detecting anti-SARS-CoV-2 antibodies. The antigen (either spike or RBD) and epitopes of the prototype SARS-CoV-2 coated in some immunoassays may no longer reflect the sequence of circulating variants. On the other hand, anti-SARS-CoV-2 antibodies elicited by highly mutated SARS-CoV-2 variants may no longer be efficiently recognized by the currently available commercial immunoassays. Therefore, beside the compelling need to regularly re-evaluate and revalidate all commercially available immunoassays against live virus neutralization assays based on emerging VoCs or VoIs, diagnostic companies may also consider to redevelop their methods, replacing former SARS-CoV-2 antigens and epitopes with those of the new variants.

MultiInflammatory Syndrome in Children: A View into Immune Pathogenesis from a Laboratory Perspective.

BACKGROUND: Multiinflammatory syndrome in children (MIS-C) is a novel and rare inflammatory disorder associated with severe acute respiratory syndrome coronavirus 2 infection in school-age children. Reports in the past year have suggested a multisystem pathophysiology characterized by hyperinflammation, gastrointestinal distress, and cardiovascular complications. Clinical laboratory investigations, including routine blood testing for inflammatory (e.g., C-reactive protein, ferritin) and cardiac (e.g., troponin, brain natriuretic peptides) markers have provided insight into potential drivers of disease pathogenesis, highlighting the role of the laboratory in the differential diagnosis of patients presenting with similar conditions (e.g., Kawasaki disease, macrophage activating syndrome). CONTENT: While few studies have applied high-dimensional immune profiling to further characterize underlying MIS-C pathophysiology, much remains unknown regarding predisposing risk factors, etiology, and long-term impact of disease onset. The extent of autoimmune involvement is also unclear. In the current review, we summarize and critically evaluate available literature on potential pathogenic mechanisms underlying MIS-C onset and discuss the current and anticipated value of various laboratory testing paradigms in MIS-C diagnosis and monitoring. SUMMARY: From initial reports, it is clear that MIS-C has unique inflammatory signatures involving both adaptive and innate systems. Certain cytokines, inflammatory markers, and cardiac markers assist in the differentiation of MIS-C from other hyperinflammatory conditions. However, there are still major gaps in our understanding of MIS-C pathogenesis, including T cell, B cell, and innate response. It is essential that researchers not only continue to decipher initial pathogenesis but also monitor long-term health outcomes, particularly given observed presence of circulating autoantibodies with unknown impact.

IFCC interim guidelines on rapid point-of-care antigen testing for SARS-CoV-2 detection in asymptomatic and symptomatic individuals.

With an almost unremittent progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections all around the world, there is a compelling need to introduce rapid, reliable, and high-throughput testing to allow appropriate clinical management and/or timely isolation of infected individuals. Although nucleic acid amplification testing (NAAT) remains the gold standard for detecting and theoretically quantifying SARS-CoV-2 mRNA in various specimen types, antigen assays may be considered a suitable alternative, under specific circumstances. Rapid antigen tests are meant to detect viral antigen proteins in biological specimens (e.g. nasal, nasopharyngeal, saliva), to indicate current SARS-CoV-2 infection. The available assay methodology includes rapid chromatographic immunoassays, used at the point-of-care, which carries some advantages and drawbacks compared to more conventional, instrumentation-based, laboratory immunoassays. Therefore, this document by the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 aims to summarize available data on the performance of currently available SARS-CoV-2 antigen rapid detection tests (Ag-RDTs), providing interim guidance on clinical indications and target populations, assay selection, and evaluation, test interpretation and limitations, as well as on pre-analytical considerations. This document is hence mainly aimed to assist laboratory and regulated health professionals in selecting, validating, and implementing regulatory approved Ag-RDTs.

Setting minimum clinical performance specifications for tests based on disease prevalence and minimum acceptable positive and negative predictive values: Practical considerations applied to COVID-19 testing.

OBJECTIVES: Several guidelines for the evaluation of laboratory tests for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection have recommended establishing an a priori definition of minimum clinical performance specifications before test selection and method evaluation. METHODS: Using positive (PPV) and negative predictive values (NPV), we constructed a spreadsheet tool for determining the minimum clinical specificity (conditional on NPV or PPV, sensitivity and prevalence) and minimum clinical sensitivity (conditional on NPV or PPV, specificity and prevalence) of tests. RESULTS: At a prevalence of 1%, there are no minimum sensitivity requirements to achieve a desired NPV of 60%-95% for a given clinical specificity above 20%. It is not possible to achieve 60-95% PPV even with 100% clinical sensitivity, except when the clinical specificity is near 100%. The opposite trend is seen in high prevalence settings (60%), where a relatively low minimum clinical sensitivity is required to achieve a desired PPV for a given clinical specificity, and a higher minimum clinical specificity is required to achieve a desired NPV for a given clinical sensitivity. DISCUSSION: The selection of laboratory tests and the testing strategy for SARS-CoV-2 involves delicate trade-offs between NPV and PPV based on prevalence and clinical sensitivity and clinical specificity. Practitioners and health authorities should carefully consider the clinical scenarios under which the test result will be used and select the most appropriate testing strategy that fulfils the a priori defined clinical performance specification.

Molecular, serological, and biochemical diagnosis and monitoring of COVID-19: IFCC taskforce evaluation of the latest evidence.

The global coronavirus disease 2019 (COVID-19) has presented major challenges for clinical laboratories, from initial diagnosis to patient monitoring and treatment. Initial response to this pandemic involved the development, production, and distribution of diagnostic molecular assays at an unprecedented rate, leading to minimal validation requirements and concerns regarding their diagnostic accuracy in clinical settings. In addition to molecular testing, serological assays to detect antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now becoming available from numerous diagnostic manufacturers. In both cases, the lack of peer-reviewed data and regulatory oversight, combined with general misconceptions regarding their appropriate use, have highlighted the importance of laboratory professionals in robustly validating and evaluating these assays for appropriate clinical use. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 has been established to synthesize up-to-date information on the epidemiology, pathogenesis, and laboratory diagnosis and monitoring of COVID-19, as well as to develop practical recommendations on the use of molecular, serological, and biochemical tests in disease diagnosis and management. This review summarizes the latest evidence and status of molecular, serological, and biochemical testing in COVID-19 and highlights some key considerations for clinical laboratories operating to support the global fight against this ongoing pandemic. Confidently this consolidated information provides a useful resource to laboratories and a reminder of the laboratory's critical role as the world battles this unprecedented crisis.

Biosafety measures for preventing infection from COVID-19 in clinical laboratories: IFCC Taskforce Recommendations.

Coronavirus disease 2019 (COVID-19) is the third coronavirus outbreak that has emerged in the past 20 years, after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). One important aspect, highlighted by many global health organizations, is that this novel coronavirus outbreak may be especially hazardous to healthcare personnel, including laboratory professionals. Therefore, the aim of this document, prepared by the COVID-19 taskforce of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), is to provide a set of recommendations, adapted from official documents of international and national health agencies, on biosafety measures for routine clinical chemistry laboratories that operate at biosafety levels 1 (BSL-1; work with agents posing minimal threat to laboratory workers) and 2 (BSL-2; work with agents associated with human disease which pose moderate hazard). We believe that the interim measures proposed in this document for best practice will help minimazing the risk of developing COVID-19 while working in clinical laboratories.

IFCC Interim Guidelines on Biochemical/Hematological Monitoring of COVID-19 Patients.

Routine biochemical and hematological tests have been reported to be useful in the stratification and prognostication of pediatric and adult patients with diagnosed coronavirus disease (COVID-19), correlating with poor outcomes such as the need for mechanical ventilation or intensive care, progression to multisystem organ failure, and/or death. While these tests are already well established in most clinical laboratories, there is still debate regarding their clinical value in the management of COVID-19, particularly in pediatrics, as well as the value of composite clinical risk scores in COVID-19 prognostication. This document by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 provides interim guidance on: (A) clinical indications for testing, (B) recommendations for test selection and interpretation, (C) considerations in test interpretation, and (D) current limitations of biochemical/hematological monitoring of COVID-19 patients. These evidence-based recommendations will provide practical guidance to clinical laboratories worldwide, underscoring the contribution of biochemical and hematological testing to our collective pandemic response.

IFCC Interim Guidelines on Serological Testing of Antibodies against SARS-CoV-2.

Serological testing for the detection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is emerging as an important component of the clinical management of patients with coronavirus disease 2019 (COVID-19) as well as the epidemiological assessment of SARS-CoV-2 exposure worldwide. In addition to molecular testing for the detection of SARS-CoV-2 infection, clinical laboratories have also needed to increase testing capacity to include serological evaluation of patients with suspected or known COVID-19. While regulatory approved serological immunoassays are now widely available from diagnostic manufacturers globally, there is significant debate regarding the clinical utility of these tests, as well as their clinical and analytical performance requirements prior to application. This document by the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 provides interim guidance on: (A) clinical indications and target populations, (B) assay selection, (C) assay evaluation, and (D) test interpretation and limitations for serological testing of antibodies against SARS-CoV-2 infection. These evidence-based recommendations will provide practical guidance to clinical laboratories in the selection, verification, and implementation of serological assays and are of the utmost importance as we expand our pandemic response from initial case tracing and containment to mitigation strategies to minimize resurgence and further morbidity and mortality.

IFCC Interim Guidelines on Molecular Testing of SARS-CoV-2 Infection.

The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection globally has relied extensively on molecular testing, contributing vitally to case identification, isolation, contact tracing, and rationalization of infection control measures during the coronavirus disease 2019 (COVID-19) pandemic. Clinical laboratories have thus needed to verify newly developed molecular tests and increase testing capacity at an unprecedented rate. As the COVID-19 pandemic continues to pose a global health threat, laboratories continue to encounter challenges in the selection, verification, and interpretation of these tests. This document by the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 provides interim guidance on: (A) clinical indications and target populations, (B) assay selection, (C) assay verification, and (D) test interpretation and limitations for molecular testing of SARS-CoV-2 infection. These evidence-based recommendations will provide practical guidance to clinical laboratories worldwide and highlight the continued importance of laboratory medicine in our collective pandemic response.

Staff rostering, split team arrangement, social distancing (physical distancing) and use of personal protective equipment to minimize risk of workplace transmission during the COVID-19 pandemic: A simulation study.

BACKGROUND: The recent global survey promoted by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 (coronavirus disease 2019) described staff rostering and organization as significant operational challenges during the COVID-19 pandemic. METHOD: A discrete event simulation was used to explore the impact of different permutations of staff roster, including the number of shifts per day, the number of staff on duty per shift, overall number of staff accessible to work in the laboratory (i.e. overall staff pool), the frequency of shift changes (i.e. number of consecutive days worked), fixed work-rest days and split team arrangement on workplace transmission of COVID-19 by a simulated index staff who acquired the infection from the community over 21 days. Additionally, the impact of workplace social distancing (physical distancing) and use of personal protective equipment (PPE) were investigated. RESULTS: A higher rate of transmission was associated with smaller overall staff pool (expressed as multiples of the number of staff per shift), higher number of shifts per day, higher number of staff per shift, and longer consecutive days worked. Having fixed work-rest arrangement did not significantly reduce the transmission rate unless the workplace outbreak was prolonged. Social distancing and PPE use significantly reduced the transmission rate. CONCLUSION: Laboratories should consider organizing the staff into smaller teams/shift and reduce the number of consecutive days worked. Additionally, our observation aligns with the IFCC biosafety recommendation of monitoring staff health (to detect early infection), split team arrangement, workplace social distancing and use of PPE.

Pathophysiology of COVID-19: Mechanisms Underlying Disease Severity and Progression.

The global epidemiology of coronavirus disease 2019 (COVID-19) suggests a wide spectrum of clinical severity, ranging from asymptomatic to fatal. Although the clinical and laboratory characteristics of COVID-19 patients have been well characterized, the pathophysiological mechanisms underlying disease severity and progression remain unclear. This review highlights key mechanisms that have been proposed to contribute to COVID-19 progression from viral entry to multisystem organ failure, as well as the central role of the immune response in successful viral clearance or progression to death.

Operational considerations and challenges of biochemistry laboratories during the COVID-19 outbreak: an IFCC global survey.

Objectives: The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 conducted a global survey to understand how biochemistry laboratories manage the operational challenges during the coronavirus disease 2019 (COVID-19) pandemic. Materials and methods: An electronic survey was distributed globally to record the operational considerations to mitigate biosafety risks in the laboratory. Additionally, the laboratories were asked to indicate the operational challenges they faced. Results: A total of 1210 valid submissions were included in this analysis. Most of the survey participants worked in hospital laboratories. Around 15% of laboratories restricted certain tests on patients with clinically suspected or confirmed COVID-19 over biosafety concerns. Just over 10% of the laboratories had to restrict their test menu or services due to resource constraints. Approximately a third of laboratories performed temperature monitoring, while two thirds of laboratories increased the frequency of disinfection. Just less than 50% of the laboratories split their teams. The greatest reported challenge faced by laboratories during the COVID-19 pandemic is securing sufficient supplies of personal protective equipment (PPE), analytical equipment, including those used at the point of care, as well as reagents, consumables and other laboratory materials. This was followed by having inadequate staff, managing their morale, anxiety and deployment. Conclusions: The restriction of tests and services may have undesirable clinical consequences as clinicians are deprived of important information to deliver appropriate care to their patients. Staff rostering and biosafety concerns require longer-term solutions as they are crucial for the continued operation of the laboratory during what may well be a prolonged pandemic.