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Id Subject Object Predicate Lexical cue
T1 0-78 Sentence denotes Diagnostic Testing for Severe Acute Respiratory Syndrome–Related Coronavirus-2
T2 79-97 Sentence denotes A Narrative Review
T3 98-131 Sentence denotes Diagnostic Testing for SARS–CoV-2
T4 133-141 Sentence denotes Abstract
T5 142-352 Sentence denotes Diagnostic testing to identify persons infected with severe acute respiratory syndrome–related coronavirus-2 (SARS–CoV-2) infection is central to control the global pandemic of COVID-19 that began in late 2019.
T6 353-482 Sentence denotes In a few countries, the use of diagnostic testing on a massive scale has been a cornerstone of successful containment strategies.
T7 483-608 Sentence denotes In contrast, the United States, hampered by limited testing capacity, has prioritized testing for specific groups of persons.
T8 609-783 Sentence denotes Real-time reverse transcriptase polymerase chain reaction–based assays performed in a laboratory on respiratory specimens are the reference standard for COVID-19 diagnostics.
T9 784-868 Sentence denotes However, point-of-care technologies and serologic immunoassays are rapidly emerging.
T10 869-1176 Sentence denotes Although excellent tools exist for the diagnosis of symptomatic patients in well-equipped laboratories, important gaps remain in screening asymptomatic persons in the incubation phase, as well as in the accurate determination of live viral shedding during convalescence to inform decisions to end isolation.
T11 1177-1326 Sentence denotes Many affluent countries have encountered challenges in test delivery and specimen collection that have inhibited rapid increases in testing capacity.
T12 1327-1389 Sentence denotes These challenges may be even greater in low-resource settings.
T13 1390-1531 Sentence denotes Urgent clinical and public health needs currently drive an unprecedented global effort to increase testing capacity for SARS–CoV-2 infection.
T14 1532-1679 Sentence denotes Here, the authors review the current array of tests for SARS–CoV-2, highlight gaps in current diagnostic capacity, and propose potential solutions.
T15 1681-1784 Sentence denotes Diagnostic testing to identify infected persons is central to efforts to control the COVID-19 pandemic.
T16 1785-1960 Sentence denotes This review synthesizes current knowledge of diagnostic options available to clinicians, highlights key gaps in current diagnostic capacity, and discusses potential solutions.
T17 1962-1980 Sentence denotes Key Summary Points
T18 1981-2090 Sentence denotes The COVID-19 pandemic demonstrates the essential role of diagnostics in the control of communicable diseases.
T19 2091-2313 Sentence denotes Laboratory-based molecular assays for detecting SARS–CoV-2 in respiratory specimens are the current reference standard for COVID-19 diagnosis, but point-of-care technologies and serologic immunoassays are rapidly emerging.
T20 2314-2429 Sentence denotes Early, massive deployment of SARS–CoV-2 diagnostics for case finding helped curb the epidemic in several countries.
T21 2430-2540 Sentence denotes Urgent clinical and public health needs now drive an unprecedented global effort to increase testing capacity.
T22 2542-2647 Sentence denotes In December 2019, a cluster of patients with pneumonia of unknown cause was reported in Wuhan, China (1).
T23 2648-2810 Sentence denotes The causative pathogen was subsequently identified as severe acute respiratory syndrome–related coronavirus-2 (SARS–CoV-2) (2), a newly described betacoronavirus.
T24 2811-2936 Sentence denotes This virus, now recognized as the etiologic agent of COVID-19 disease, is the seventh known coronavirus to infect humans (1).
T25 2937-3040 Sentence denotes Since the recognition of COVID-19, there has been an exponential rise in the number of cases worldwide.
T26 3041-3178 Sentence denotes As of 1 April 2020, the World Health Organization reported more than 926 000 cases in more than 195 countries, areas, or territories (3).
T27 3179-3467 Sentence denotes Reasons for the rapid spread include high transmissibility of the virus (4, 5), especially among asymptomatic or minimally symptomatic carriers (6, 7); the apparent absence of any cross-protective immunity from related viral infections; and delayed public health response measures (8–10).
T28 3468-3576 Sentence denotes Age and the presence of comorbid illnesses increase the risk for death among persons with COVID-19 (11, 12).
T29 3577-3748 Sentence denotes The clinical manifestations of COVID-19 in children are less severe compared with adults, yet age younger than 1 year seems to increase the risk for critical illness (13).
T30 3749-3920 Sentence denotes Current case-fatality rate estimates range from 0.6% to 7.2% by region and seem to be substantially higher than the 0.1% mortality rate of seasonal influenza (12, 14, 15).
T31 3921-4126 Sentence denotes However, current estimates of COVID-19 case-fatality rates are probably inflated because of preferential testing in many countries of persons with severe manifestations, who are at risk for death (12, 16).
T32 4127-4284 Sentence denotes In Germany and South Korea, the case-fatality rates are less than 0.5%, probably because extensive testing revealed a large denominator of mild illness (17).
T33 4285-4452 Sentence denotes It has been estimated that before the wide-scale travel restrictions in China, undiagnosed SARS–CoV-2 represented the infection source for 79% of documented cases (7).
T34 4453-4562 Sentence denotes These observations underscore the critical importance of ample, accurate diagnostic testing in this pandemic.
T35 4563-4701 Sentence denotes Here, we review the current array of tests for SARS–CoV-2, highlight gaps in current diagnostic capacity, and propose potential solutions.
T36 4703-4710 Sentence denotes Methods
T37 4711-4786 Sentence denotes We searched the PubMed database for articles on SARS–CoV-2 and diagnostics.
T38 4787-5413 Sentence denotes The Medical Subject Headings (MeSH) search terms used were “Coronavirus”[MeSH]; “Coronavirus Infections”[MeSH]; “Severe Acute Respiratory Syndrome”[MeSH]; “Betacoronavirus”[MeSH]; “SARS Virus”[MeSH]; “Polymerase Chain Reaction”[MeSH]; “Reverse Transcriptase Polymerase Chain Reaction”[MeSH]; “High-Throughput Nucleotide Sequencing”[MeSH]; “Sensitivity and Specificity”[MeSH]; “Point-of-Care Testing”[MeSH]; “Antigens”[MeSH]; “Serology”[MeSH]; “Immunoglobulin G”[MeSH]; “Immunoglobulin M”[MeSH]; “Clustered Regularly Interspaced Short Palindromic Repeats”[MeSH]; “CRISPR-Cas Systems”[MESH]; and “Diagnosis, Differential”[MESH].
T39 5414-5629 Sentence denotes Non-MeSH search terms used were covid, SARS, SARS-CoV, pcr, digital droplet PCR, next generation sequencing, point-of-care test, antigen, analyte, serology, Immunoglobulin, CRISPR-CAS, Diagnos, and turn around time.
T40 5630-5728 Sentence denotes Only articles including human subjects and those published from 2003 to the present were included.
T41 5729-5794 Sentence denotes Articles in languages other than English or French were excluded.
T42 5795-5866 Sentence denotes We screened the results on title and abstract for relevant information.
T43 5867-6051 Sentence denotes Starting from the articles found in this search, we used a snowball search strategy, scanning useful references and similar articles and retrieving those that were considered relevant.
T44 6052-6114 Sentence denotes Furthermore, experts were consulted for additional literature.
T45 6115-6201 Sentence denotes Guidelines and resources from international organizations were used where appropriate.
T46 6202-6247 Sentence denotes This search was last updated on 1 April 2020.
T47 6249-6306 Sentence denotes The Role of Diagnostic Testing in the SARS–CoV-2 Pandemic
T48 6307-6496 Sentence denotes The primary goal of epidemic containment is to reduce disease transmission by reducing the number of susceptible persons in the population or by reducing the basic reproductive number (R0).
T49 6497-6678 Sentence denotes This number is modulated by such factors as the duration of viral shedding, the infectiousness of the organism, and the contact matrix between infected and susceptible persons (18).
T50 6679-6859 Sentence denotes Given the lack of effective vaccines or treatments (19), the only currently available lever to reduce SARS–CoV-2 transmission is to identify and isolate persons who are contagious.
T51 6860-6928 Sentence denotes Deployment of SARS–CoV-2 testing has varied widely across the globe.
T52 6929-7050 Sentence denotes A few Asian countries have illustrated the power of preparedness, flexible isolation systems, and intensive case finding.
T53 7051-7149 Sentence denotes South Korea dramatically slowed the epidemic by implementing an unprecedented testing effort (20).
T54 7150-7318 Sentence denotes Using innovative measures, South Korea performed more than 300 000 tests (5828.6 tests per million persons) in the 9 weeks after the first case was identified (20, 21).
T55 7319-7406 Sentence denotes Singapore used a broad case definition, aggressive contact tracing, and isolation (10).
T56 7407-7681 Sentence denotes Moreover, to identify infected persons not meeting the case definition, Singapore screened patients with pneumonia and influenza-like illnesses in hospitals and primary care settings, severely ill patients in intensive care, and deaths with a possible infectious cause (10).
T57 7682-7732 Sentence denotes Taiwan and Hong Kong used similar approaches (22).
T58 7733-7881 Sentence denotes These countries rapidly deployed resource-intensive strategies that prioritized aggressive testing and isolation to interrupt transmission (20, 22).
T59 7882-8064 Sentence denotes In the face of widespread transmission, the role of diagnostic testing is contingent on the type of testing available, the resources required for testing, and time to obtain results.
T60 8065-8288 Sentence denotes For example, rapidly identifying cases among hospitalized patients remains a high priority to properly allocate personal protective equipment and to prevent nosocomial spread with subsequent community transmission (23, 24).
T61 8289-8395 Sentence denotes Likewise, specific treatment decisions and enrollment in ongoing clinical trials require prompt diagnosis.
T62 8397-8416 Sentence denotes Diagnostic Testing:
T63 8417-8439 Sentence denotes Defining Key Use Cases
T64 8440-8634 Sentence denotes Despite the remarkable speed with which accurate diagnostic tests have been developed and made available for SARS–CoV-2 (25), current tools only partially meet several clinically relevant needs.
T65 8635-8749 Sentence denotes Figure 1 illustrates different indications for diagnostic testing among persons with proven or suspected COVID-19.
T66 8750-8861 Sentence denotes For each of these, the most important consideration is the clinical decision a test result will help to inform.
T67 8862-9329 Sentence denotes Test designs must account for several parameters, such as whether the test detects infection directly (such as the virus itself) or indirectly (such as host antibodies), test turnaround time, the ability to perform many tests at the same time (that is, throughput), the need to have a minimum number of specimens before testing (that is, batching), and the ability to perform the test in low-infrastructure settings (such as on cruise ships or in remote communities).
T68 9330-9400 Sentence denotes The potential for use at the point of care depends on test complexity.
T69 9401-9409 Sentence denotes The U.S.
T70 9410-9494 Sentence denotes Food and Drug Administration (FDA) categorizes diagnostic tests by their complexity:
T71 9495-9630 Sentence denotes Waived tests are available for use at the point of care, whereas moderate- and high-complexity tests must be performed in a laboratory.
T72 9631-9707 Sentence denotes The intended use also determines which specimen types are ideal or feasible.
T73 9708-9827 Sentence denotes Finally, it is important to recognize that the acceptable diagnostic accuracy of a test may vary according to use case.
T74 9828-10097 Sentence denotes For example, sensitivity and specificity requirements of an assay used to confirm results of a screening test need not be as stringent as those of a method used for standalone diagnosis, because the pool of persons being tested is already enriched with true infections.
T75 10098-10260 Sentence denotes The Foundation for Innovative New Diagnostics has published a detailed assessment of priority use cases to be considered by test developers and policymakers (26).
T76 10261-10270 Sentence denotes Figure 1.
T77 10272-10365 Sentence denotes Examples of use cases for diagnostic testing among persons with proven or suspected COVID-19.
T78 10366-10578 Sentence denotes A test well suited for one use case (such as epidemiologic surveillance) may be completely inadequate for another (such as rapid screening of symptomatic patients for allocation of personal protective equipment).
T79 10579-10814 Sentence denotes For test results to enable a specific clinical decision, test developers, policymakers, and clinicians need to consider each of these with respect to the intention of testing and the population being tested as specifically as possible.
T80 10815-11102 Sentence denotes For the moment, most use cases placed above the green and gray bar are best met by nucleic acid amplification tests, whereas detection of host-derived antibodies directed against SARS–CoV-2 will be crucial for surveillance, epidemic forecasting, and determination of SARS–CoV-2 immunity.
T81 11103-11172 Sentence denotes SARS–CoV-2 = severe acute respiratory syndrome–related coronavirus-2.
T82 11174-11186 Sentence denotes Who to Test:
T83 11187-11242 Sentence denotes Current Diagnostic Recommendations in the United States
T84 11243-11448 Sentence denotes In response to the rapidly evolving COVID-19 pandemic, countries have used different testing approaches depending on testing capacity, public health resources, and the spread of the virus in the community.
T85 11449-11625 Sentence denotes In the United States, diagnostic testing indications and capacity were limited at the beginning of the outbreak, largely because of regulatory hurdles for the use of new tests.
T86 11626-11762 Sentence denotes To expand access to testing, the FDA released policies to allow laboratories to use their validated assays in a more timely manner (27).
T87 11763-11967 Sentence denotes On 4 March, the Centers for Disease Control and Prevention (CDC) removed restrictive testing criteria, recommending that clinicians use their judgment to determine whether a test should be performed (28).
T88 11968-12080 Sentence denotes Because testing capacity remains suboptimal (27), the implementation of this recommendation remains a challenge.
T89 12081-12426 Sentence denotes The CDC still recommends priority for testing 3 groups: hospitalized patients with presentations compatible with COVID-19, other symptomatic persons at risk for poor outcomes, and persons who had close contact with someone with suspected or confirmed COVID-19 within 14 days of illness onset or have a history of travel in an affected area (28).
T90 12427-12515 Sentence denotes These patients should be evaluated with a molecular diagnostic test, as described later.
T91 12516-12572 Sentence denotes The CDC does not recommend testing asymptomatic persons.
T92 12574-12586 Sentence denotes How to Test:
T93 12587-12630 Sentence denotes Diagnostic Tests in Use or Under Evaluation
T94 12631-12914 Sentence denotes Although real-time reverse transcriptase polymerase chain reaction (RT-PCR)–based assays performed in the laboratory on respiratory specimens are the cornerstone of COVID-19 diagnostic testing, several novel or complementary diagnostic methods are being developed and evaluated (16).
T95 12915-13024 Sentence denotes Figure 2 depicts the adequacy of the principal assay types used or proposed for COVID-19 for 4 key use cases.
T96 13025-13183 Sentence denotes Among patients diagnosed with COVID-19, the occurrence of concomitant viral infections has been reported to range from below 6% (29) to greater than 60% (30).
T97 13184-13298 Sentence denotes As a result, it is not possible to rule out SARS–CoV-2 infection merely by detecting another respiratory pathogen.
T98 13299-13308 Sentence denotes Figure 2.
T99 13310-13392 Sentence denotes Heat map showing the adequacy of principal assay types (rows) for 4 key use cases.
T100 13393-13502 Sentence denotes * This assumes that assays in development or currently undergoing regulatory evaluation prove to be accurate.
T101 13503-13698 Sentence denotes † The utility of antibody detection assays for diagnosing acute infections is probably very limited around the time of symptom onset, when viral shedding and transmission risk seem to be highest.
T102 13699-13838 Sentence denotes Thus, although such tests may have a role among persons presenting late in the course of their infection, the potential for misuse is high.
T103 13840-13874 Sentence denotes Laboratory-Based Molecular Testing
T104 13875-14109 Sentence denotes The current diagnostic strategy recommended by the CDC to identify patients with COVID-19 is to test samples taken from the respiratory tract to assess for the presence of 1 or several nucleic acid targets specific to SARS–CoV-2 (25).
T105 14110-14284 Sentence denotes A nasopharyngeal specimen is the preferred choice for swab-based SARS–CoV-2 testing, but oropharyngeal, mid-turbinate, or anterior nares samples also are acceptable (31, 32).
T106 14285-14410 Sentence denotes Samples should be obtained by using a flocked swab, if available, to enhance the collection and release of cellular material.
T107 14411-14465 Sentence denotes Swabs with an aluminum or plastic shaft are preferred.
T108 14466-14599 Sentence denotes Swabs that contain calcium alginate, wood, or cotton should be avoided, because they may contain substances that inhibit PCR testing.
T109 14600-14736 Sentence denotes Ideally, swabs should be transferred into universal transport medium immediately after sample collection to preserve viral nucleic acid.
T110 14737-14965 Sentence denotes Samples taken from sputum, endotracheal aspirates, and bronchoalveolar lavage also may be sent directly to the microbiology laboratory for processing, and may have greater sensitivity than upper respiratory tract specimens (33).
T111 14966-15031 Sentence denotes Inadequate sample collection may result in a false-negative test.
T112 15032-15142 Sentence denotes After specimen collection, samples undergo RNA extraction followed by qualitative RT-PCR for target detection.
T113 15143-15225 Sentence denotes In the United States, the CDC has developed the most widely used SARS–CoV-2 assay.
T114 15226-15398 Sentence denotes The kit contains PCR primer–probe sets for 2 regions of the viral nucleocapsid gene (N1 and N2), and for the human RNase P gene to ensure the RNA extraction was successful.
T115 15399-15564 Sentence denotes This assay differs from the World Health Organization primer–probe sets, which target the SARS–CoV-2 RNA-dependent RNA polymerase (RdRP) and envelope (E) genes (25).
T116 15565-15798 Sentence denotes Both assays have high analytic sensitivity and specificity for SARS–CoV-2, with minimal cross-reactivity with other circulating strains of coronaviruses, and both use a cycle threshold of less than 40 as the criterion for positivity.
T117 15799-16082 Sentence denotes The CDC kit may be used by state public health laboratories, other laboratories determined by the state to be qualified, and clinical laboratories that meet the regulatory requirements of the Clinical Laboratories Improvement Amendment (CLIA) to perform high-complexity testing (27).
T118 16083-16217 Sentence denotes Dozens of laboratories have applied for Emergency Use Authorization (EUA) from the FDA for their own laboratory-developed assays (34).
T119 16218-16372 Sentence denotes The FDA also has granted an EUA for several commercial assays (35), further expanding the ability of clinical laboratories to use these platforms (Table).
T120 16373-16379 Sentence denotes Table.
T121 16380-16780 Sentence denotes The 28 Commercial SARS–CoV-2 in Vitro Diagnostic Assays Given an EUA From the FDA as of 4 April 2020 The lack of an established reference standard, use of differing sample collection and preparation methods, and an incomplete understanding of viral dynamics across the time course of infection hamper rigorous assessment of the diagnostic accuracy of the many newly introduced SARS–CoV-2 assays (36).
T122 16781-16894 Sentence denotes Serum and urine are usually negative for the presence of viral nucleic acid, regardless of illness severity (33).
T123 16895-17056 Sentence denotes Of importance, the ability of RT-PCR assays to rule out COVID-19 on the basis of upper respiratory tract samples obtained at a single time point remains unclear.
T124 17057-17305 Sentence denotes Conversely, after a patient has had a positive test result, several authorities have recommended obtaining at least 2 negative upper respiratory tract samples, collected at intervals of 24 hours or longer, to document SARS–CoV-2 clearance (37, 38).
T125 17307-17342 Sentence denotes Point-of-Care Molecular Diagnostics
T126 17343-17734 Sentence denotes Low-complexity, rapid (results within 1 hour) molecular diagnostic tests for respiratory viral infections that are CLIA waived (FDA approved for use outside the laboratory by nonlaboratory personnel) include cartridge-based assays on platforms that include the Abbott ID NOW (Abbott Laboratories), BioFire FilmArray (bioMérieux), cobas Liat (Roche Diagnostics), and GeneXpert (Cepheid) (39).
T127 17735-17855 Sentence denotes Rapid point-of-care assays for SARS–CoV-2 on instruments such as these will be critical to expand point-of-care testing.
T128 17856-18077 Sentence denotes The Xpert Xpress SARS–CoV-2 test (Cepheid) has received an FDA EUA and is performed on the GeneXpert platform, which is already widely used for tuberculosis and HIV testing, especially in low- and middle-income countries.
T129 18078-18295 Sentence denotes This capacity might be useful to scale up testing across the world as well as in settings where rapid results at the point of care would enable clinical decisions, although testing throughput may be a limiting factor.
T130 18297-18320 Sentence denotes Antigen Detection Tests
T131 18321-18577 Sentence denotes Tests that detect respiratory syncytial virus or influenza virus antigens by immunoassay directly from clinical specimens have been commercially available for decades, are of low complexity, and may provide results within minutes at the point of care (40).
T132 18578-18844 Sentence denotes Current tools for influenza and respiratory syncytial virus suffer from suboptimal sensitivity to rule out disease (41, 42); the same challenge would probably exist for SARS–CoV-2, and tests would need to be implemented with clear guidance on correct interpretation.
T133 18845-18978 Sentence denotes Prototypes of such tests for other novel coronaviruses have not received regulatory approval (43, 44) but are under development (45).
T134 18979-19142 Sentence denotes Monoclonal antibodies against the nucleocapsid protein of SARS–CoV-2 have been generated, which might form the basis of a future rapid antigen detection test (20).
T135 19144-19152 Sentence denotes Serology
T136 19153-19447 Sentence denotes Serologic tests that identify antibodies (such as IgA, IgM, and IgG) to SARS–CoV-2 from clinical specimens (such as blood or saliva), such as enzyme-linked immunosorbent assays, may be less complex than molecular tests and have the potential to be used for diagnosis in certain situations (46).
T137 19448-19623 Sentence denotes However, their utility for diagnosing acute infections is probably limited around the time of symptom onset, when viral shedding and transmission risk seem to be highest (32).
T138 19624-19706 Sentence denotes Antibody responses to infection take days to weeks to be reliably detectable (46).
T139 19707-19823 Sentence denotes Negative results would not exclude SARS–CoV-2 infection, particularly among those with recent exposure to the virus.
T140 19824-20029 Sentence denotes Cross-reactivity of antibody to non–SARS–CoV-2 coronavirus proteins is also a potential problem, whereby positive results may be the result of past or present infection with other human coronaviruses (47).
T141 20030-20242 Sentence denotes Serologic assays might be more relevant in scenarios in which patients present to medical care with late complications of disease, when RT-PCR may be falsely negative, because viral shedding drops over time (48).
T142 20243-20488 Sentence denotes The development of serologic assays that accurately assess prior infection and immunity to SARS–CoV-2 will be essential for epidemiologic studies, ongoing surveillance, vaccine studies, and potentially for risk assessment of health care workers.
T143 20489-20610 Sentence denotes Immunoassays are already on the market in some countries, but their diagnostic accuracy and optimal use remain undefined.
T144 20612-20638 Sentence denotes Ancillary Diagnostic Tests
T145 20639-20743 Sentence denotes The optimal use of diagnostic imaging, biomarkers, and other nonmicrobiologic tests is rapidly evolving.
T146 20745-20763 Sentence denotes Radiographic Tests
T147 20764-20835 Sentence denotes Many centers have evaluated the utility of chest imaging for diagnosis.
T148 20836-20993 Sentence denotes On chest radiography, bilateral pneumonia is the most frequently reported feature (range, 11.8% to 100%) and is more common than a unilateral focus (49, 50).
T149 20994-21162 Sentence denotes Computed tomography is regarded as more sensitive than radiography, with several cohort studies reporting that most patients (77.8% to 100%) had ground glass opacities.
T150 21163-21329 Sentence denotes Other features commonly reported with COVID-19 on chest computed tomography include a peripheral distribution, fine reticular opacities, and vascular thickening (51).
T151 21330-21506 Sentence denotes Compared with serial nasopharyngeal sampling, chest computed tomography may be more sensitive than an RT-PCR test at a single time point for the diagnosis of COVID-19 (52, 53).
T152 21507-21639 Sentence denotes In addition, artificial intelligence may help distinguish COVID-19 from other etiologic agents of community-acquired pneumonia (54).
T153 21640-21771 Sentence denotes However, these findings are not completely specific to COVID-19 and do not exclude a co-infection or an alternative diagnosis (55).
T154 21773-21817 Sentence denotes Biomarkers Associated With COVID-19 Patients
T155 21818-22128 Sentence denotes The most common laboratory features reported in patients with COVID-19 include decreased albumin (75.8% [95% CI, 30.5% to 100%]), elevated C-reactive protein (58.3% [CI, 21.8% to 94.7%]), and elevated lactate dehydrogenase levels (57.0% [CI, 38.0% to 76.0%]), and lymphopenia (43.1% [CI, 18.9% to 67.3%]) (56).
T156 22129-22394 Sentence denotes Other biomarkers that have been reported include increased erythrocyte sedimentation rates; elevated aspartate aminotransferase, alanine aminotransferase, and creatinine kinase levels; leukopenia; leukocytosis; and increased bilirubin and creatinine levels (57–59).
T157 22395-22605 Sentence denotes Such findings are not surprising, because these biomarkers represent an inflammatory host response to SARS–CoV-2 or are early markers of end-organ dysfunction, similar to that seen in patients with sepsis (60).
T158 22606-22788 Sentence denotes No biomarker or combination of biomarkers currently exists that is sensitive or specific enough to establish a diagnosis of COVID-19, or to pragmatically predict its clinical course.
T159 22790-22834 Sentence denotes Unmet Needs and the Diagnostic Test Pipeline
T160 22836-22875 Sentence denotes Scaling Up Access to Diagnostic Testing
T161 22876-23040 Sentence denotes In the face of a public health emergency, important first steps to expand testing capacity include relaxing and streamlining regulatory requirements and procedures.
T162 23041-23268 Sentence denotes Local public health laboratories and academic diagnostic laboratories in the United States are being rapidly enabled to perform EUA-granted commercial assays and laboratory-developed tests using research use–only reagents (61).
T163 23269-23438 Sentence denotes University research laboratories could also add capacity, although concerns exist regarding quality control and the absence of protocols for managing clinical specimens.
T164 23439-23573 Sentence denotes Flexibility regarding nucleic acid extraction methods and amplification instruments when using CDC protocols is being introduced (34).
T165 23574-23732 Sentence denotes National agencies are expeditiously making materials for test development and validation available to clinical laboratories and diagnostic test manufacturers.
T166 23733-23901 Sentence denotes Safely evaluating clinically stable persons for COVID-19 at traditional health care access points is resource intensive and slow, and risks exposing staff to infection.
T167 23902-24132 Sentence denotes Many jurisdictions are enabling innovative testing venues, such as external tents or drive-through or “phone booth” testing, as well as home assessment teams to expedite specimen collection while limiting potential exposures (62).
T168 24133-24220 Sentence denotes Telemedicine combined with at-home nasal swab self-testing also has been proposed (63).
T169 24221-24412 Sentence denotes Of importance, in jurisdictions without universal health care coverage, policy solutions must be introduced to eliminate financial barriers to testing for uninsured and underinsured patients.
T170 24413-24590 Sentence denotes Efforts to increase accessibility of testing for multiple use cases need to be coupled to appropriate public health interventions to isolate infected persons and their contacts.
T171 24592-24669 Sentence denotes Alternatives to Usual Specimen Types, Collection Devices, and Transport Media
T172 24670-24743 Sentence denotes Nasopharyngeal swabs are the recommended specimen for molecular analysis.
T173 24744-24921 Sentence denotes The sudden demand for flocked nasopharyngeal swabs and viral transport medium generated by the pandemic has put enormous pressures on supply chain capacities for these products.
T174 24922-25074 Sentence denotes As of 19 March 2020 the CDC made oropharyngeal, mid-turbinate, and nasal swabs acceptable specimen types if nasopharyngeal swabs are not available (31).
T175 25075-25254 Sentence denotes Early-morning posterior oropharyngeal saliva samples (coughed up by clearing the throat) also have been assessed as useful specimen types and would not require use of a swab (48).
T176 25255-25522 Sentence denotes The CDC has released a standard operating procedure for laboratories to create their own viral transport medium (64); other solutions also may be used if viral transport medium is unavailable, including phosphate-buffered saline, liquid Amies, and normal saline (65).
T177 25523-25662 Sentence denotes The FDA has provided guidance on its Web site for alternative materials to collect and transport samples for RT-PCR SARS–CoV-2 assays (34).
T178 25663-25754 Sentence denotes The diagnostic value of molecular testing of nonrespiratory specimens currently is unclear.
T179 25756-25805 Sentence denotes Diagnostics Pipeline in the Short and Medium Term
T180 25806-26142 Sentence denotes Although excellent tools exist for the diagnosis of symptomatic patients in well-equipped laboratories, important gaps remain in screening asymptomatic persons in the incubation phase, as well as for the accurate determination of live viral shedding among patients in the convalescence phase to inform de-isolation decisions (Figure 2).
T181 26143-26263 Sentence denotes Further, it is critical to advance solutions that require less well-equipped laboratories to curb the pandemic globally.
T182 26264-26497 Sentence denotes The Foundation for Innovative New Diagnostics (FIND) and others have created online resources to collate the rapidly evolving set of assays at various stages of development, from proof of concept to full regulatory approval (20, 53).
T183 26498-26707 Sentence denotes Simple antigen-based tests, if sensitive enough, might be useful in lower-resource and home settings to inform quarantine and spatial distancing measures for patients without severe illness and their contacts.
T184 26708-27037 Sentence denotes Novel technologies, such as Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)-based diagnostics are being used to develop rapid, simple, low-cost, portable, temperature-stable assays for deployment in the field in nontraditional and resource-limited settings, such as airports and border crossings (20, 51, 54).
T185 27038-27130 Sentence denotes Other technologies might be deployed to lower-resource settings if they can be standardized.
T186 27131-27330 Sentence denotes For example, it might be possible to leverage existing loop-mediated isothermal amplification testing networks established for other diseases, such as human African trypanosomiasis surveillance (66).
T187 27332-27352 Sentence denotes Other Considerations
T188 27353-27524 Sentence denotes Critical considerations for diagnostics used for epidemic diseases of public health importance include the quality assurance and regulatory frameworks surrounding testing.
T189 27525-27741 Sentence denotes Mature regulatory agencies have developed mechanisms to account for emergencies, such as the FDA's EUA stream, but pragmatic solutions must be found to facilitate wide-scale, independent evaluation of emerging tests.
T190 27742-27903 Sentence denotes Initially, the need for elaborate biosafety precautions and inconsistent recommendations for their application across regions severely hampered COVID-19 testing.
T191 27904-28332 Sentence denotes Although these continue to evolve, current recommendations in Canada and the United States acknowledge that nonpropagative work for molecular testing may be performed in containment level 2 conditions found in routine diagnostic laboratories and provide specific guidance on diagnostic testing of specimens conducted outside a biosafety level 2 laboratory, such as rapid respiratory testing performed at the point of care (67) .
T192 28334-28344 Sentence denotes Conclusion
T193 28345-28470 Sentence denotes The COVID-19 pandemic has dramatically highlighted the essential role of diagnostics in the control of communicable diseases.
T194 28471-28587 Sentence denotes Intensive diagnostics deployment probably contributed to the success of a few countries in controlling transmission.
T195 28588-28709 Sentence denotes Urgent clinical and public health needs now drive an unprecedented global effort to increase SARS–CoV-2 testing capacity.
T196 28710-28855 Sentence denotes Finally, the blinding speed with which COVID-19 has spread illustrates the need for preparedness and long-term investments in diagnostic testing.
T197 28857-28915 Sentence denotes This article was published at Annals.org on 13 April 2020.
T198 28916-28931 Sentence denotes Acknowledgment:
T199 28932-29122 Sentence denotes The authors thank Professor Ellen Jo Baron for insightful comments on earlier versions of this manuscript and Ms. Chelsea Caya for assistance with literature searches and assembling figures.
T200 29123-29137 Sentence denotes Grant Support:
T201 29138-29239 Sentence denotes Drs. Papenburg, Quach, and Yansouni have received career awards from the Québec Health Research Fund.
T202 29240-29252 Sentence denotes Disclosures:
T203 29253-29607 Sentence denotes Dr. Cheng reports grants from the Canadian Institute of Health Research and McGill Interdisciplinary Initiative in Infection and Immunity during the conduct of the study; after the manuscript was written and submitted, he was offered a position on the scientific advisory board of GEn1E Lifesciences, but this position is unrelated to the submitted work.
T204 29608-29841 Sentence denotes Dr. Papenburg reports grants and personal fees from BD Diagnostics, Seegene, and AbbVie; personal fees from Cepheid; and grants from MedImmune, Sanofi Pasteur, Janssen Pharmaceuticals, and Hoffman–La Roche outside the submitted work.
T205 29842-29920 Sentence denotes Dr. Kanjilal reports grants from PhAST Diagnostics outside the submitted work.
T206 29921-29999 Sentence denotes Dr. Libman reports grants from GeoSentinel Network outside the submitted work.
T207 30000-30085 Sentence denotes Dr. Yansouni reports nonfinancial support from bioMérieux outside the submitted work.
T208 30086-30149 Sentence denotes Authors not named here have disclosed no conflicts of interest.
T209 30150-30258 Sentence denotes Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-1301.
T210 30259-30280 Sentence denotes Editors' Disclosures:
T211 30281-30418 Sentence denotes Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics.
T212 30419-30428 Sentence denotes Darren B.
T213 30429-30538 Sentence denotes Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose.
T214 30539-30549 Sentence denotes Cynthia D.
T215 30550-30652 Sentence denotes Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose.
T216 30653-30660 Sentence denotes Jaya K.
T217 30661-30758 Sentence denotes Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer.
T218 30759-30771 Sentence denotes Christina C.
T219 30772-30862 Sentence denotes Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center.
T220 30863-30872 Sentence denotes Sankey V.
T221 30873-30974 Sentence denotes Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose.
T222 30975-31085 Sentence denotes Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
T223 31086-31107 Sentence denotes Corresponding Author:
T224 31108-31118 Sentence denotes Matthew P.
T225 31119-31298 Sentence denotes Cheng, MDCM, Division of Infectious Diseases, McGill University Health Centre, 1001 Decarie Boulevard, E05.1709, Montreal, Quebec, Canada H4A 3J1; e-mail, matthew.cheng@mcgill.ca.
T226 31299-31377 Sentence denotes Current author addresses and author contributions are available at Annals.org.
T227 31378-31403 Sentence denotes Current Author Addresses:
T228 31404-31554 Sentence denotes Dr. Cheng, MDCM, Division of Infectious Diseases, McGill University Health Centre, 1001 Decarie Boulevard, E05.1709, Montreal, Quebec, Canada H4A 3J1.
T229 31555-31569 Sentence denotes Dr. Papenburg:
T230 31570-31700 Sentence denotes Division of Infectious Diseases, Montreal Children's Hospital, 1001 Decarie Boulevard, E05.1905, Montreal, Quebec, Canada H4A 3J1.
T231 31701-31716 Sentence denotes Dr. Desjardins:
T232 31717-31834 Sentence denotes Division of Transplant Infectious Disease, Brigham and Women's Hospital, 75 Francis Street, PBB-A4, Boston, MA 02115.
T233 31835-31848 Sentence denotes Dr. Kanjilal:
T234 31849-31999 Sentence denotes Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Drive, Suite 401, East Boston, MA 02115.
T235 32000-32010 Sentence denotes Dr. Quach:
T236 32011-32072 Sentence denotes Divison of Infectious Diseases, CHU Sainte-Justine, 3175, ch.
T237 32073-32136 Sentence denotes Côte Ste-Catherine, B.17.102, Montreal, Quebec, Canada H3T 1C5.
T238 32137-32148 Sentence denotes Dr. Libman:
T239 32149-32282 Sentence denotes Division of Infectious Diseases, McGill University Health Centre, 1001 Decarie Boulevard, E05.1830, Montreal, Quebec, Canada H4A 3J1.
T240 32283-32296 Sentence denotes Dr. Dittrich:
T241 32297-32407 Sentence denotes Foundation of Innovative New Diagnostics (FIND), Campus Biotech, Chemin des Mines 91 202, Geneva, Switzerland.
T242 32408-32421 Sentence denotes Dr. Yansouni:
T243 32422-32555 Sentence denotes Division of Infectious Diseases, McGill University Health Centre, 1001 Decarie Boulevard, EM3.3242, Montreal, Quebec, Canada H4A 3J1.
T244 32556-32577 Sentence denotes Author Contributions:
T245 32578-32605 Sentence denotes Conception and design: M.P.
T246 32606-32615 Sentence denotes Cheng, J.
T247 32616-32629 Sentence denotes Papenburg, M.
T248 32630-32644 Sentence denotes Desjardins, M.
T249 32645-32655 Sentence denotes Libman, S.
T250 32656-32670 Sentence denotes Dittrich, C.P.
T251 32671-32680 Sentence denotes Yansouni.
T252 32681-32726 Sentence denotes Analysis and interpretation of the data: M.P.
T253 32727-32736 Sentence denotes Cheng, J.
T254 32737-32750 Sentence denotes Papenburg, S.
T255 32751-32765 Sentence denotes Dittrich, C.P.
T256 32766-32775 Sentence denotes Yansouni.
T257 32776-32805 Sentence denotes Drafting of the article: M.P.
T258 32806-32815 Sentence denotes Cheng, J.
T259 32816-32829 Sentence denotes Papenburg, M.
T260 32830-32844 Sentence denotes Desjardins, S.
T261 32845-32857 Sentence denotes Kanjilal, M.
T262 32858-32868 Sentence denotes Libman, S.
T263 32869-32883 Sentence denotes Dittrich, C.P.
T264 32884-32893 Sentence denotes Yansouni.
T265 32894-32952 Sentence denotes Critical revision for important intellectual content: M.P.
T266 32953-32962 Sentence denotes Cheng, J.
T267 32963-32976 Sentence denotes Papenburg, M.
T268 32977-32991 Sentence denotes Desjardins, S.
T269 32992-33004 Sentence denotes Kanjilal, C.
T270 33005-33014 Sentence denotes Quach, M.
T271 33015-33027 Sentence denotes Libman, C.P.
T272 33028-33037 Sentence denotes Yansouni.
T273 33038-33073 Sentence denotes Final approval of the article: M.P.
T274 33074-33083 Sentence denotes Cheng, J.
T275 33084-33097 Sentence denotes Papenburg, M.
T276 33098-33112 Sentence denotes Desjardins, S.
T277 33113-33125 Sentence denotes Kanjilal, C.
T278 33126-33135 Sentence denotes Quach, M.
T279 33136-33146 Sentence denotes Libman, S.
T280 33147-33161 Sentence denotes Dittrich, C.P.
T281 33162-33171 Sentence denotes Yansouni.
T282 33172-33198 Sentence denotes Obtaining of funding: C.P.
T283 33199-33208 Sentence denotes Yansouni.
T284 33209-33261 Sentence denotes Administrative, technical, or logistic support: C.P.
T285 33262-33271 Sentence denotes Yansouni.
T286 33272-33309 Sentence denotes Collection and assembly of data: M.P.
T287 33310-33319 Sentence denotes Cheng, J.
T288 33320-33335 Sentence denotes Papenburg, C.P.
T289 33336-33345 Sentence denotes Yansouni.