BACKGROUND: Rapid, accessible, and accurate testing was paramount to an effective US COVID-19 response. Federal partners supported SARS-CoV-2 testing scale-up through an interagency-coordinated approach that focused on expanding supply chains, research and development, validation, and improving patient access. We aimed to provide an overview of the federal efforts to scale up the testing response and study the impact of scale-up. METHODS: In this descriptive analysis, we mapped federal partner activities and milestones using the US Government Testing and Diagnostics Working Group (TDWG) and participating agency and department data from Jan 1, 2020, to Dec 31, 2022. Tests produced (TDWG), reported test positivity (US Centers for Disease Control and Prevention [CDC]'s COVID-19 Electronic Laboratory Reporting system and the Federal Direct Report testing data), reported COVID-19 case counts (CDC), hospitalisations (Department of Health and Human Services Unified Hospital Data Surveillance System and the CDC's National Healthcare Safety Network), and deaths (CDC) were analysed over time. We then developed an agent-based model to evaluate the impact testing had on COVID-19 outcomes using different scenarios. The scenarios were (1) if efforts led to substantially fewer tests produced, (2) if scale-up was delayed, affecting test access, and (3) if efforts led to substantially more tests produced. FINDINGS: Approximately 6·7 billion SARS-CoV-2 tests, including over 1·5 billion laboratory-based, 1·9 billion point-of-care (POC), and 3·2 billion over-the-counter (OTC) tests, were produced, and approximately 2·7 billion tests were performed between Jan 1, 2020, and Dec 31, 2022. Testing capacity exhibited various expansion phases, with laboratory-based capacity growing from approximately 6 million tests per month in March, 2020 to approximately 34 million tests per month in July, 2020; POC increased to approximately 126 million tests per month by December, 2020, and OTC increased to approximately 986 million tests per month by February, 2022. Comparison between the baseline (actual) and delay-in-testing scenario suggests the increased testing capacity potentially saved upwards of 1·4 million lives and averted 7 million hospitalisations. INTERPRETATION: Our study suggests that early development, manufacturing, and distribution of tests had a great impact on reducing severe COVID-19 outcomes. These results highlight the importance of robust and rapid test development, production, and distribution when addressing future public health threats. FUNDING: US Administration for Strategic Preparedness and Response and US Centers for Disease Control and Prevention.

CONTEXT: The first case of mpox was detected in the United States in a Laboratory Response Network (LRN) laboratory at the Massachusetts Department of Public Health on May 17, 2022. Through previous years of smallpox preparedness efforts by the United States government, testing capacity in LRN laboratories across the United States utilizing the FDA-cleared Centers for Disease Control and Prevention (CDC) Non-variola orthopoxvirus (NVO) test was approximately 6000 tests weekly across the nation prior to the mpox outbreak. By early June 2022, the LRN laboratories had capacity to perform up to 8000 tests per week. As the outbreak expanded, cases were identified in every United States state, peaking at ~3000 cases per week nationally in August 2022. OBJECTIVE: Although NVO testing capacity in LRN laboratories exceeded national mpox testing demand overall, LRN testing access in some areas was challenged and test expansion was necessary. PARTICIPANTS: CDC engaged with partners and select commercial laboratories early to increase diagnostic testing access by allowing these commercial laboratories to utilize the NVO test. SETTING: The expansion of testing to commercial laboratories increased testing availability, capacity, and volume nationwide. This was the first time that CDC shared an FDA 510k-cleared molecular test with commercial laboratories to support a public health emergency. DESIGN: Extensive efforts were made to ensure the CDC NVO test was used appropriately in the private sector and that the transfer process met regulatory requirements. MAIN OUTCOME MEASURES, RESULTS, CONCLUSIONS: These novel methods to expand NVO testing to commercial laboratories increased national testing capacity to 80 000 mpox tests/week. Test volumes among these laboratories never exceeded this expanded capacity. The rapid increase in the nation's testing capacity, in conjunction and coordination with other public and private health efforts, helped to detect cases rapidly. These actions demonstrated the importance of highly functional and efficient public health and private sector partnerships for responding to public health emergencies.

During routine clinical practice, infectious disease physicians encounter patients with difficult-to-diagnose clinical syndromes and may order advanced molecular testing to detect pathogens. These tests may identify potential infectious causes for illness and allow clinicians to adapt treatments or stop unnecessary antimicrobials. Cases of pathogen-agnostic disease testing also provide an important window into known, emerging, and reemerging pathogens and may be leveraged as part of national sentinel surveillance. A survey of Emerging Infections Network members, a group of infectious disease providers in North America, was conducted in May 2023. The objective of the survey was to gain insight into how and when infectious disease physicians use advanced molecular testing for patients with difficult-to-diagnose infectious diseases, as well as to explore the usefulness of advanced molecular testing and barriers to use. Overall, 643 providers answered at least some of the survey questions; 478 (74%) of those who completed the survey had ordered advanced molecular testing in the last two years, and formed the basis for this study. Respondents indicated that they most often ordered broad-range 16S rRNA gene sequencing, followed by metagenomic next-generation sequencing and whole genome sequencing; and commented that in clinical practice, some, but not all tests were useful. Many physicians also noted several barriers to use, including a lack of national guidelines and cost, while others commented that whole genome sequencing had potential for use in outbreak surveillance. Improving frontline physician access, availability, affordability, and developing clear national guidelines for interpretation and use of advanced molecular testing could potentially support clinical practice and public health surveillance.

To better identify emerging or reemerging pathogens in patients with difficult-to-diagnose infections, it is important to improve access to advanced molecular testing methods. This is particularly relevant for cases where conventional microbiologic testing has been unable to detect the pathogen and the patient's specimens test negative. To assess the availability and utility of such testing for human clinical specimens, a literature review of published biomedical literature was conducted. From a corpus of more than 4,000 articles, a set of 34 reports was reviewed in detail for data on where the testing was being performed, types of clinical specimens tested, pathogen agnostic techniques and methods used, and results in terms of potential pathogens identified. This review assessed the frequency of advanced molecular testing, such as metagenomic next generation sequencing that has been applied to clinical specimens for supporting clinicians in caring for difficult-to-diagnose patients. Specimen types tested were from cerebrospinal fluid, respiratory secretions, and other body tissues and fluids. Publications included case reports and series, and there were several that involved clinical trials, surveillance studies, research programs, or outbreak situations. Testing identified both known human pathogens (sometimes in new sites) and previously unknown human pathogens. During this review, there were no apparent coordinated efforts identified to develop regional or national reports on emerging or reemerging pathogens. Therefore, development of a coordinated sentinel surveillance system that applies advanced molecular methods to clinical specimens which are negative by conventional microbiological diagnostic testing would provide a foundation for systematic characterization of emerging and underdiagnosed pathogens and contribute to national biodefense strategy goals.

The surveillance and identification of emerging, reemerging, and unknown infectious disease pathogens is essential to national public health preparedness and relies on fluidity, coordination, and interconnectivity between public and private pathogen surveillance systems and networks. Developing a national sentinel surveillance network with existing resources and infrastructure could increase efficiency, accelerate the identification of emerging public health threats, and support coordinated intervention strategies that reduce morbidity and mortality. However, implementing and sustaining programs to detect emerging and reemerging pathogens in humans using advanced molecular methods, such as metagenomic sequencing, requires making large investments in testing equipment and developing networks of clinicians, laboratory scientists, and bioinformaticians. In this study, we sought to gain an understanding of how federal government agencies currently support such pathogen agnostic testing of human specimens in the United States. We conducted a landscape analysis of federal agency websites for publicly accessible information on the availability and type of pathogen agnostic testing and details on flow of clinical specimens and data. The website analysis was supplemented by an expert review of results with representatives from the federal agencies. Operating divisions within the US Department of Health and Human Services and the US Department of Veterans Affairs have developed and sustained extensive clinical and research networks to obtain patient specimens and perform metagenomic sequencing. Metagenomic facilities supported by US agencies were not equally geographically distributed across the United States. Although many entities have work dedicated to metagenomics and/or support emerging infectious disease surveillance specimen collection, there was minimal formal collaboration across agencies.

Self-tests* to detect current infection with SARS-CoV-2, the virus that causes COVID-19, are valuable tools that guide individual decision-making and risk reduction() (1-3). Increased self-test use (4) has likely contributed to underascertainment of COVID-19 cases (5-7), because unlike the requirements to report results of laboratory-based and health care provider-administered point-of-care COVID-19 tests,() public health authorities do not require reporting of self-test results. However, self-test instructions include a recommendation that users report results to their health care provider so that they can receive additional testing and treatment if clinically indicated.() In addition, multiple manufacturers of COVID-19 self-tests have developed websites or companion mobile applications for users to voluntarily report self-test result data. Federal agencies use the data reported to manufacturers, in combination with manufacturing supply chain information, to better understand self-test availability and use. This report summarizes data voluntarily reported by users of 10.7 million self-tests from four manufacturers during October 31, 2021-June 11, 2022, and compares these self-test data with data received by CDC for 361.9 million laboratory-based and point-of-care tests performed during the same period. Overall trends in reporting volume and percentage of positive results, as well as completeness of reporting demographic variables, were similar across test types. However, the limited amount and quality of data reported from self-tests currently reduces their capacity to augment existing surveillance. Self-tests provide important risk-reduction information to users, and continued development of infrastructure and methods to collect and analyze data from self-tests could improve their use for surveillance during public health emergencies.

Diagnostic stewardship means ordering the right tests, for the right patient at the right time to inform optimal clinical care. Diagnostic stewardship is an integral part of antibiotic stewardship efforts to optimize antibiotic use and improve patient outcomes, including reductions in antibiotic resistance, and treatment of sepsis. CDC's Division of Healthcare Quality Promotion (DHQP) hosted a meeting on improving patient safety through diagnostic stewardship with a focus on the use of the laboratory. The meeting identified emerging issues in the field of diagnostic stewardship, raised awareness of these issues among stakeholders, and discussed strategies and interventions to address the issues-all with an emphasis on improved outcomes and patient safety. This white paper summarizes the key takeaways of the meeting including needs for diagnostic stewardship implementation, promising future avenues for diagnostic stewardship implementation, and areas of needed research.

Patient care and public health require timely, reliable laboratory testing. However, clinical laboratory professionals rarely know whether patient specimens contain infectious agents, making ensuring biosafety while performing testing procedures challenging. The importance of biosafety in clinical laboratories was highlighted during the 2014 Ebola outbreak, where concerns about biosafety resulted in delayed diagnoses and contributed to patient deaths. This review is a collaboration between subject matter experts from large and small laboratories and the federal government to evaluate the capability of clinical laboratories to manage biosafety risks and safely test patient specimens. We discuss the complexity of clinical laboratories, including anatomic pathology, and describe how applying current biosafety guidance may be difficult as these guidelines, largely based on practices in research laboratories, do not always correspond to the unique clinical laboratory environments and their specialized equipment and processes. We retrospectively describe the biosafety gaps and opportunities for improvement in the areas of risk assessment and management; automated and manual laboratory disciplines; specimen collection, processing, and storage; test utilization; equipment and instrumentation safety; disinfection practices; personal protective equipment; waste management; laboratory personnel training and competency assessment; accreditation processes; and ethical guidance. Also addressed are the unique biosafety challenges successfully handled by a Texas community hospital clinical laboratory that performed testing for patients with Ebola without a formal biocontainment unit. The gaps in knowledge and practices identified in previous and ongoing outbreaks demonstrate the need for collaborative, comprehensive solutions to improve clinical laboratory biosafety and to better combat future emerging infectious disease outbreaks.

BACKGROUND: There is a need for validated and standardized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quantitative immunoglobulin G (IgG) and neutralization assays that can be used to understand the immunology and pathogenesis of SARS-CoV-2 infection and support the coronavirus disease 2019 (COVID-19) pandemic response. METHODS: Literature searches were conducted to identify English language publications from peer-reviewed journals and preprints from January 2020 through November 6, 2020. Relevant publications were reviewed for mention of IgG or neutralization assays for SARS-CoV-2, or both, and the methods of reporting assay results. RESULTS: Quantitative SARS-CoV-2 IgG results have been reported from a limited number of studies; most studies used in-house laboratory-developed tests in limited settings, and only two semiquantitative tests have received US Food and Drug Administration (FDA) Emergency Use Authorization (EUA). As of November 6, 2020, there is only one SARS-CoV-2 neutralization assay with FDA EUA. Relatively few studies have attempted correlation of quantitative IgG titers with neutralization results to estimate surrogates of protection. The number of individuals tested is small compared with the magnitude of the pandemic, and persons tested are not representative of disproportionately affected populations. Methods of reporting quantitative results are not standardized to enable comparisons and meta-analyses. CONCLUSIONS: Lack of standardized SARS-CoV-2 quantitative IgG and neutralization assays precludes comparison of results from published studies. Interassay and interlaboratory validation and standardization of assays will support efforts to better understand antibody kinetics and longevity of humoral immune responses postillness, surrogates of immune protection, and vaccine immunogenicity and efficacy. Public-private partnerships could facilitate realization of these advances in the United States and worldwide.

Hurricane Maria made landfall in Puerto Rico on September 20, 2017, causing major damage to infrastructure and severely limiting access to potable water, electric power, transportation, and communications. Public services that were affected included operations of the Puerto Rico Department of Health (PRDOH), which provides critical laboratory testing and surveillance for diseases and other health hazards. PRDOH requested assistance from CDC for the restoration of laboratory infrastructure, surveillance capacity, and diagnostic testing for selected priority diseases, including influenza, rabies, leptospirosis, salmonellosis, and tuberculosis. PRDOH, CDC, and the Association of Public Health Laboratories (APHL) collaborated to conduct rapid needs assessments and, with assistance from the CDC Foundation, implement a temporary transport system for shipping samples from Puerto Rico to the continental United States for surveillance and diagnostic and confirmatory testing. This report describes the initial laboratory emergency response and engagement efforts among federal, state, and nongovernmental partners to reestablish public health laboratory services severely affected by Hurricane Maria. The implementation of a sample transport system allowed Puerto Rico to reinitiate priority infectious disease surveillance and laboratory testing for patient and public health interventions, while awaiting the rebuilding and reinstatement of PRDOH laboratory services.