Temporary Regulatory Deviations and the Coronavirus Disease 2019 (COVID-19) PCR Labeling Update Study Indicate What Laboratory-Developed Test Regulation by the US Food and Drug Administration (FDA) Could Look Like.

The coronavirus disease 2019 (COVID-19) response necessitated innovations and a series of regulatory deviations that also affected laboratory-developed tests (LDTs). To examine real-world consequences and specify regulatory paradigm shifts, legislative proposals were aligned on a common timeline with Emergency Use Authorization (EUA) of LDTs and the US Food and Drug Administration (FDA)-orchestrated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) labeling update study. The initial EUA adoption by LDT developers shows that the FDA can have oversight over LDTs. We used efficiency-corrected microcosting of our EUA PCR assay to estimate the national cost of the labeling update study to $0.3 to $1.4 million US dollars. Labeling update study performance data showed lower average detection limits in commercial in vitro diagnostic (IVD) assays versus LDTs (32,000 ± 75,000 versus 71,000 ± 147,000 nucleic acid amplification tests/mL; P = 0.04); however, comparison also shows that FDA review of IVD assays and LDTs did not prevent differences between initial and labeling update performance (IVD assay, P < 0.0001; LDT, P = 0.003). The regulatory shifts re-emphasized that both commercial tests and LDTs rely heavily on laboratory competence and procedures; however, lack of performance data on authorized tests, when clinically implemented, precludes assessment of the benefit related to regulatory review. Temporary regulatory deviations during the pandemic and regulatory science tools (ie, reference material) have generated valuable real-world evidence to inform pending legislation regarding LDT regulation.

Differential impact of the COVID-19 pandemic on laboratory reporting of norovirus and Campylobacter in England: A modelling approach.

BACKGROUND: The COVID-19 pandemic has impacted surveillance activities for multiple pathogens. Since March 2020, there was a decline in the number of reports of norovirus and Campylobacter recorded by England's national laboratory surveillance system. The aim is to estimate and compare the impact of the COVID-19 pandemic on norovirus and Campylobacter surveillance data in England. METHODS: We utilised two quasi-experimental approaches based on a generalised linear model for sequential count data. The first approach estimates overall impact and the second approach focuses on the impact of specific elements of the pandemic response (COVID-19 diagnostic testing and control measures). The following time series (27, 2015-43, 2020) were used: weekly laboratory-confirmed norovirus and Campylobacter reports, air temperature, conducted Sars-CoV-2 tests and Index of COVID-19 control measures stringency. RESULTS: The period of Sars-CoV-2 emergence and subsequent sustained transmission was associated with persistent reductions in norovirus laboratory reports (p = 0.001), whereas the reductions were more pronounced during pandemic emergence and later recovered for Campylobacter (p = 0.075). The total estimated reduction was 47% - 79% for norovirus (12-43, 2020). The total reduction varied by time for Campylobacter, e.g. 19% - 33% in April, 1% - 7% in August. CONCLUSION: Laboratory reporting of norovirus was more adversely impacted than Campylobacter by the COVID-19 pandemic. This may be partially explained by a comparatively stronger effect of behavioural interventions on norovirus transmission and a relatively greater reduction in norovirus testing capacity. Our study underlines the differential impact a pandemic may have on surveillance of gastrointestinal infectious diseases.

Pathological Features in 100 Deceased Patients With COVID-19 in Correlation With Clinical and Laboratory Data.

Background: Autopsies on COVID-19 deceased patients have many limitations due to necessary epidemiologic and preventative measures. The ongoing pandemic has caused a significant strain on healthcare systems and is being extensively studied around the world. Clinical data does not always corelate with post-mortem findings. The goal of our study was to find pathognomonic factors associated with COVID-19 mortality in 100 post-mortem full body autopsies. Materials and Methods: Following necessary safety protocol, we performed 100 autopsies on patients who were diagnosed with COVID-19 related death. The macroscopic and microscopic pathologies were evaluated along with clinical and laboratory findings. Results: Extensive coagulopathic changes are seen throughout the bodies of diseased patients. Diffuse alveolar damage is pathognomonic of COVID-19 viral pneumonia, and is the leading cause of lethal outcome in younger patients. Extrapulmonary pathology is predominantly seen in the liver and spleen. Intravascular thrombosis is often widespread and signs of septic shock are often present. Conclusion: The described pathological manifestations of COVID-19 in deceased patients are an insight into the main mechanisms of SARS-CoV-2 associated lethal outcome. The disease bears no obvious bias in severity, but seems to be more severe in some patients, hinting at genetic or epigenetic factors at play.

Understanding the Barriers to Pooled SARS-CoV-2 Testing in the United States.

Pooled testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is instrumental for increasing test capacity while decreasing test cost. Pooled testing programs permit sustainable, long-term surveillance measures, which are essential for the early detection of virus resurgence in communities or the emergence of variants of concern. While numerous pooled approaches have been proposed to increase test capacity, uptake by laboratories has been limited. On 9 December 2020, we invited 362 U.S. laboratories that inquired about the Yale School of Public Health SalivaDirect test to participate in a survey to evaluate testing constraints and pooling strategies for SARS-CoV-2 testing. The survey was distributed using Qualtrics, and three reminders were sent. The survey closed on 21 January 2021. Of 93 responses received (25.7% response rate), 90 were from Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories conducting SARS-CoV-2 testing. The remaining three were excluded from the analyses. Responses indicated that the major barriers to the uptake of pooled testing in the United States may not simply be the number of tests a laboratory can process per day, but rather the lack of clear protocols and adequate resources; laboratories are working with fixed physical and human capital constraints. Importantly, laboratories across the country are heterogeneous in infrastructure and workflow. The need for SARS-CoV-2 testing will remain for years to come. Testing programs can be maintained through pooled PCR testing strategies, and while statisticians, operations researchers, and others with expertise in sampling design have important value to add, laboratories require support on how to transition from traditional diagnostic testing to pooled surveillance. IMPORTANCE While numerous pooled SARS-CoV-2 testing approaches have been described in an effort to increase testing capacity and decrease test prices, uptake by laboratories has been limited. Responses to our survey of United States-based laboratories highlight the importance of consulting end-users-those that solutions are being designed for-so challenges can be addressed in a manner tailored to meet the specific needs out in the field. It may be surprising to those designing pooled testing strategies to learn that laboratories view pooling as more time-consuming than testing samples individually, and therefore that it is thought to create delays in test reporting.

The considerable impact of the SARS-CoV-2 pandemic and COVID-19 on the UK National Mycology Reference Laboratory activities and workload.

Starting late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic of coronavirus-19 disease (COVID-19) with ∼179 million cases and ∼3.9 million deaths to date. COVID-19 ranges from asymptomatic infection to severe illness with acute respiratory distress requiring critical care in up to 40% of hospitalized patients. Numerous reports have identified COVID-19-associated pulmonary aspergillosis (CAPA) as an important infective complication of COVID-19. In the UK, the pandemic has had unprecedented impacts on the National Health Service (NHS'): each wave of infections required hospitals to reconfigure for large surges in patients requiring intensive care, to the detriment of most aspects of non-COVID care including planned operations, outpatient appointments, general practitioner consultations and referrals. The UK National Mycology Reference Laboratory (MRL) offers a comprehensive service for the diagnosis and management of fungal disease nationwide, with a test portfolio that includes: diagnosis of allergies to fungal and other respiratory allergens; diagnosis of superficial and invasive/systemic fungal infections using traditional mycological, serological and molecular approaches; identification and susceptibility testing of the causative fungi; therapeutic drug monitoring of patients receiving antifungal therapy. Here, we describe the impact of the first 14 months of the COVID-19 pandemic on MRL activities. Changes to MRL workload closely mirrored many of the NHS-wide challenges, with marked reductions in 'elective' mycological activities unrelated to the pandemic and dramatic surges in tests that contributed to the diagnosis and management of COVID-19-related secondary fungal infections, in particular CAPA and candidemia in COVID-19 patients in intensive care. LAY SUMMARY: The COVID-19 pandemic has had an unprecedented impact on the UK National Health Service, with hospitals forced to repeatedly reconfigure to prepare for large surges in COVID-19 patients. Here we describe the impact of the first 14 months of the UK pandemic on the workload of the National Mycology Reference Laboratory.

Evaluation of the Clinical Performance of 7 Serological Assays for SARS-CoV-2 for Use in Clinical Laboratories.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological assays have emerged as a response to the global pandemic, warranting studies evaluating their clinical performance. This study investigated 7 commercially available SARS-CoV-2 serological assays in samples from noninfected individuals and hospitalized patients. METHODS: SARS-CoV-2 qualitative serological assays by Abbott (IgG), Beckman (IgG), DiaSorin (IgG), EUROIMMUN (IgG and IgA), Roche and Bio-Rad (Total) were evaluated using specimens collected pre-December 2019 (n = 393), from nucleic acid amplification testing (NAAT) negative patients (n = 40), and from 53 patients with COVID-19 by NAAT collected 3-21 days post-onset of symptoms (POS) (N = 83). Negative agreement (NA), positive agreement (PA), and positive and negative predictive values (PPV and NPV) at prevalences of 5% and 10% were calculated. RESULTS: The overall %NA; 95% CI in the negative samples were: Roche 99.8%; 99.3-100.2, Beckman 99.8%; 98.7-100.0, Abbott and Bio-Rad 99.3%; 98.0-99.9, DiaSorin 98.4; 97.2-99.6, EUROIMMUN IgG 97.5%; 95.5-98.7, and EUROIMMUN IgA 79.7%; 75.9-83.5), accounting for positive/equivocal results as false positives. The %PA; 95% CI in samples collected 14+ days POS (n = 24) were: Bio-Rad 83.3%; 68.4-98.2, Abbott and Roche 79.2%; 62.9-95.4, EUROIMMUN IgA 70.8%; 52.6-89.0, Beckman 58.3%; 38.6-78.1, DiaSorin 54.2; 34.2-74.1, and EUROIMMUN IgG 50.0%; 30.0-70.0, accounting for negative/equivocal results as false negatives. NPVs ranged from 97.4%-98.9% and 94.7%-97.7% for prevalences 5% and 10%, respectively. PPVs ranged from 15.5%-94.8% and 27.9%-97.4% for prevalences 5% and 10%, respectively. CONCLUSION: The Roche and Beckman assays resulted in fewer false positives, followed by the Bio-Rad and Abbott assays. While the Bio-Rad assay demonstrated higher antibody detection in COVID-19-positive patients, PA claims cannot be established with a high level of confidence in our sample population.

COVID-19 laboratory preparedness and response in the Americas Region: Lessons learned.

By the time the etiologic agent of the COVID-19 was identified as a novel coronavirus, no country in the Americas Region had laboratory capacity for detecting this new virus. A strategic multilevel approach with specific reagent purchase and delivery, regional trainings, in-country missions, and the provision of technical support was established for timely preparedness of national reference laboratories for SARS-CoV-2 detection. All countries should be prepared to timely detect any potential pandemic emerging agent. The rapid SARS-CoV-2 molecular detection implementation throughout the Americas showed the importance of an efficient and coordinated laboratory response for preparedness. Here we present how in 25 days the Americas Region went from no SARS-CoV-2 diagnostic capacity, to molecular detection fully implemented in 28 Member States, under the coordinated strategy of the Pan American Health Organization and collaborative work at regional and country level with national authorities and public health laboratories.

Initial Clinical Laboratory Response to COVID-19: A Survey of Medical Laboratory Professionals.

OBJECTIVE: To explore the experiences of medical laboratory professionals (MLPs) and their perceptions of the needs of clinical laboratories in response to COVID-19. METHODS: We surveyed laboratory professionals working in United States clinical laboratories during the initial months of the pandemic. RESULTS: Overall clinical laboratory testing and overtime work for laboratorians decreased during the first months of the pandemic. Laboratory professionals reported better or unchanged job satisfaction, feelings toward their work, and morale in their workplace, which were related to healthcare facility and laboratory leadership response. They reported receiving in-kind gifts, but no hazard pay, for their essential work. Important supply needs included reagents and personal protective equipment (PPE). CONCLUSION: The response by healthcare facilities and laboratory leadership can influence MLPs job satisfaction, feelings toward their work, and laboratory morale during a pandemic. Current COVID-19 laboratory testing management, in the absence of sufficient reagents and supplies, cannot fully address the needs of clinical laboratories.

Simple nomogram based on initial laboratory data for predicting the probability of ICU transfer of COVID-19 patients: Multicenter retrospective study.

This retrospective, multicenter study investigated the risk factors associated with intensive care unit (ICU) admission and transfer in 461 adult patients with confirmed coronavirus disease 2019 (COVID-19) hospitalized from 22 January to 14 March 2020 in Hunan, China. Outcomes of ICU and non-ICU patients were compared, and a simple nomogram for predicting the probability of ICU transfer after hospital admission was developed based on initial laboratory data using a Cox proportional hazards regression model. Differences in laboratory indices were observed between patients admitted to the ICU and those who were not admitted. Several independent predictors of ICU transfer in COVID-19 patients were identified including older age (≥65 years) (hazard ratio [HR] = 4.02), hypertension (HR = 2.65), neutrophil count (HR = 1.11), procalcitonin level (HR = 3.67), prothrombin time (HR = 1.28), and D-dimer level (HR = 1.25). The lymphocyte count and albumin level were negatively associated with mortality (HR = 0.08 and 0.86, respectively). The developed model provides a means for identifying, at hospital admission, the subset of patients with COVID-19 who are at high risk of progression and would require transfer to the ICU within 3 and 7 days after hospitalization. This method of early patient triage allows a more effective allocation of limited medical resources.

Expanding molecular diagnostic capacity for COVID-19 in Ethiopia: operational implications, challenges and lessons learnt.

Efforts towards slowing down coronavirus (COVID-19) transmission and reducing mortality have focused on timely case detection, isolation and treatment. Availability of laboratory COVID-19 testing capacity using reverse-transcriptase polymerase chain reaction (RT-PCR) was essential for case detection. Hence, it was critical to establish and expand this capacity to test for COVID-19 in Ethiopia. To this end, using a three-phrased approach, potential public and private laboratories with RT-PCR technology were assessed, capacitated with trained human resource and equipped as required. These laboratories were verified to conduct COVID-19 testing with quality assurance checks regularly conducted. Within a 10-month period, COVID-19 testing laboratories increased from zero to 65 in all Regional States with the capacity to conduct 18,454 tests per day. The success of this rapid countrywide expansion of laboratory testing capacity for COVID-19 depended on some key operational implications: the strong laboratory coordination network within the country, the use of non-virologic laboratories, investment in capacity building, digitalization of the data for better information management and establishing quality assurance checks. A weak supply chain for laboratory reagents and consumables, differences in the brands of COVID-19 test kits, frequent breakdowns of the PCR machines and inadequate number of laboratory personnel following the adaption of a 24/7 work schedule were some of the challenges experienced during the process of laboratory expansion. Overall, we learn that multisectoral involvement of laboratories from non-health sectors, an effective supply chain system with an insight into the promotion of local production of laboratory supplies were critical during the laboratory expansion for COVID-19 testing. The consistent support from WHO and other implementing partners to Member States is needed in building the capacity of laboratories across different diagnostic capabilities in line with International Health Regulations. This will enable efficient adaptation to respond to future public health emergencies.

Acceptance of a Symptom-Based Approach for COVID-19 rtRT-PCR Testing to Conserve Resources in a Lower Middle-Income Setting.

SARS-CoV-2 initially emerged in Wuhan, China in late 2019. It has since been recognized as a pandemic and has led to great social and economic disruption globally. The Reverse Transcriptase Real-Time Polymerase Chain Reaction (rtRT-PCR) has become the primary method for COVID-19 testing worldwide. The method requires a specialized laboratory set up. Long-term persistence of SARS-CoV-2 RNA in nasopharyngeal secretion after full clinical recovery of the patient is regularly observed nowadays. This forces the patients to spend a longer period in isolation and test repeatedly to obtain evidence of viral clearance. Repeated COVID-19 testing in asymptomatic or mildly symptomatic cases often leads to extra workload for laboratories that are already struggling with a high specimen turnover. Here, we present 5 purposively selected cases with different patterns of clinical presentations in which nasopharyngeal shedding of SARS-CoV-2 RNA was observed in patients for a long time. From these case studies, we emphasized the adoption of a symptom-based approach for discontinuing transmission-based precautions over a test-based strategy to reduce the time spent by asymptomatic and mildly symptomatic COVID-19 patients in isolation. A symptom-based approach will also help reduce laboratory burden for COVID-19 testing as well as conserve valuable resources and supplies utilized for rtRT-PCR testing in an emerging lower-middle-income setting. Most importantly, it will also make room for critically ill COVID-19 patients to visit or avail COVID-19 testing at their convenience.

The impact of biosafety enhancement on stat laboratory quality metrics: Lessons from the COVID-19 pandemic.

OBJECTIVE: It is unclear if implementation of biosafety action plans in response to the COVID-19 pandemic has affected laboratory quality metrics. METHODS: This retrospective study used quality data, including turnaround time (TAT) and number/type of unacceptable specimens from a stat laboratory supporting an outpatient medical clinic serving predominantly elderly cancer patients. Four months of data from the height of the COVID-19 pandemic (March-June 2020) were compared to the same months in 2019. RESULTS: March-May 2020 test volumes were decreased compared to 2019. June 2020 test volume was slightly increased compared to 2019. TATs in 2020 were similar/ slightly improved compared to the same months in 2019, due to shortened collect to receive and receive to verify TATs. The number and types of unacceptable specimens were similar in 2020 and 2019. CONCLUSIONS: Despite the challenges to the system caused by the pandemic, laboratory quality metrics were maintained.

Laboratory Perspective on Racial Disparities in Sexually Transmitted Infections.

BACKGROUND: Rates of sexually transmitted infections (STI) have risen steadily in recent years, and racial and ethnic minorities have borne the disproportionate burden of STI increases in the United States. Historical inequities and social determinants of health are significant contributors to observed disparities and affect access to diagnostic testing for STI. CONTENT: Public health systems rely heavily on laboratory medicine professionals for diagnosis and reporting of STI. Therefore, it is imperative that clinicians and laboratory professionals be familiar with issues underlying disparities in STI incidence and barriers to reliable diagnostic testing. In this mini-review, we will summarize contributors to racial/ethnic disparity in STI, highlight current epidemiologic trends for gonorrhea, chlamydia, and syphilis, discuss policy issues that affect laboratory and public health funding, and identify specific analytic challenges for diagnostic laboratories. SUMMARY: Racial and ethnic disparities in STI in the US are striking and are due to complex interactions of myriad social determinants of health. Budgetary cuts for laboratory and public health services and competition for resources during the COVID-19 pandemic are major challenges. Laboratory professionals must be aware of these underlying issues and work to maximize efforts to ensure equitable access to diagnostic STI testing for all persons, particularly those most disproportionately burdened by STI.

[Point-of-care testing: place of France in the world National survey in healthcare establisments in 2019]. / Examens de biologie médicale délocalisée : place de la France dans le monde Enquête nationale en 2019 dans les établissements de santé.

The point-of-care tests (POCT) are subject to accreditation. A national inventory survey provides a synthesis of knowledge. The survey distributed 31 questions in 2019. 147 responses were received (75% biologists, 49% CHU, 42% CHG). Only 20.41% are accredited ISO22870, the majority for <50% of the medical departments; 70% say they are going there at the end of 2019 or in 2020. The maps are unknown for 32% (EBMD) and 82% (TROD). Visibility is poor with: medical establishment committee (40%), IT department (31%). Connection is necessary for 87-95% depending on the criterion (QC, authorizations, etc.) and 66% of answers highlight that less than 50% of connexion is effective. The major advantage is the delay of the result (62.5%), then the relationship with the health teams (33.3%). The disadvantages: difficulty of the quality approach (45%), cost of tests (34.3%). Human resource requirements are identified for technicians (82%) and biologists (76%). The multiplicity of sites, devices and operators means that it is difficult to set up and maintain. Biology outside the laboratories, under biological responsibility, must meet a rigorous imperative quality approach.