key: cord-271920-1dzkgt6w
authors: Carpenter, Christopher R.; Mudd, Philip; West, Colin P.; Wilber, Erin; Wilber, Scott T.
title: Diagnosing COVID‐19 in the Emergency Department: A Scoping Review of Clinical Exam, Labs, Imaging Accuracy and Biases
date: 2020-06-16
journal: Acad Emerg Med
DOI: 10.1111/acem.14048
sha: 
doc_id: 271920
cord_uid: 1dzkgt6w

In December 2019 a novel viral respiratory pathogen emerged in China, ultimately named severe acute respiratory syndrome coronavirus 2 (SARS‐Co‐V‐2) with the clinical illness dubbed coronavirus disease (COVID‐19). COVID‐19 became a global pandemic in early 2020 forcing governments worldwide to enact social isolation policies with dire economic ramifications. Emergency departments (ED) encountered decreased patient volumes before some in Seattle, New York City, New Orleans, and Detroit experienced waves of COVID‐19 patients mixed with asymptomatic patients or those concerned about potential exposures. Diagnosing COVID‐19 was hampered by inadequate supplies of reagents and kits, which was compounded by clinical and radiographic features that overlap with numerous seasonal viral respiratory infections.

DR. CHRISTOPHER R. CARPENTER (Orcid ID : 0000-0002-2603-7157) Article type : Evidence-based Diagnostics

In December 2019 a novel viral respiratory pathogen emerged in China, ultimately named severe acute respiratory syndrome coronavirus 2 (SARS-Co-V-2) with the clinical illness dubbed coronavirus disease . COVID-19 became a global pandemic in early 2020 forcing governments worldwide to enact social isolation policies with dire economic ramifications.

Emergency departments (ED) encountered decreased patient volumes before some in Seattle, New York City, New Orleans, and Detroit experienced waves of COVID-19 patients mixed with asymptomatic patients or those concerned about potential exposures. Diagnosing was hampered by inadequate supplies of reagents and kits, which was compounded by clinical and radiographic features that overlap with numerous seasonal viral respiratory infections. 1 The United States (US) Food and Drug Administration (FDA) issued an emergency use authorization on February 4, 2020 to enable Centers for Disease Control (CDC)-qualified laboratories to perform COVID-19 testing. As of June 3, the FDA provided emergency use authorization for 85 commercial assays, including polymerase chain reaction tests and immunoglobulin assays. 2 Early real-time reverse transcription polymerase chain reaction (rRT-PCR) tests had false-negative (1-sensitivity) rates as high as 40%. 3 As waves of COVID-19 patients present to ED's in coming months with symptoms or potential exposures, understanding the diagnostic accuracy and reliability of history, physical exam, routine labs, advanced imaging, and an evolving array of COVID-19 diagnostics will be essential knowledge to inform the timing of testing, optimal specimen and test selection, shared decision-making, and ultimately derivation of clinical instruments to guide disposition, follow-up, and shared

This article is protected by copyright. All rights reserved decision-making choices ( Figure 1 ). 4 This review provides a narrative overview of published research with the primary objective to describe the frequency, causes, and implications of falsenegative rRT-PCR for diagnosis and surveillance. Secondary objectives include describing potential diagnostic biases in current rapid cycle COVID-19 diagnostic research reports, while providing recommendations for clinicians for interpreting results with knowledge of these design and reporting limitations. A final objective is to add context to rRT-PCR ordering and interpretation by understanding the diagnostic accuracy and additive value of history, physical exam, routine hematology and chemistry tests, computed tomography (CT), and serology for COVID-19 immunoglobulins.

This is a scoping review that adheres to PRISMA-ScR reporting recommendations. 5 The published literature was searched using strategies created by a medical librarian for COVID -19 and diagnostic accuracy. The search was implemented in PubMed 1946-and Embase 1947with a date limit from January 1, 2020 until present with an English language limit. The search strategy used a combination of standardized terms and key words, including but not limited to (Covid-19 OR Novel Coronavirus OR SARS-COV-2) AND (diagnosis OR polymerase chain reaction OR serology OR CRISPR-CAS OR sensitivity/specificity) (Appendix). The testing search was based on Cheng et al., 6 adding to this prior publication by incorporating clinical exam, imaging, and serology into the synthesis of current diagnostic research. The searches were run on April 23 and May 5, 2020 .

One author (CRC) reviewed the title and abstracts for all identified citations. Other authors reviewed the manuscripts identified and added pertinent references. Original research studies describing the frequency of history/physical exam findings or diagnostic accuracy (sensitivity, specificity, likelihood ratios) of history/physical exam, labs or imaging for COVID-19 were included. Exclusion criteria included non-English, animal research, study protocols, prevention, pathophysiology, lab processing, or policy manuscripts. Two authors (CRC, SW) abstracted

This article is protected by copyright. All rights reserved diagnostic accuracy data and reported adherence to the Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. 7 Compliance with STARD was used as a measure of research quality. The same two authors synthesized the results into summary conclusions.

A total of 1,907 citations were screened (Figure 2) . None of the studies cite or adhere completely to either the Standards for Reporting of Diagnostic Accuracy (STARD) 7 or the updated reporting framework for history and physical examination. 8 Many of these early publications are letters or case reports with uncertain editorial rigor judging by the turnaround time from initial submission to publication. Many studies rely upon rRT-PCR as the criterion standard for COVID-19, but few contemplate the possibility or likelihood of false-negative or false-positive rRT-PCR results. None of the studies discuss the possibility of various diagnostic biases (spectrum, incorporation, partial verification, differential verification, or imperfect gold standard), nor the potential skew of these biases in observed estimates of sensitivity or specificity. 9 

Fever is the most commonly reported finding in 84%-87% of COVID-19 cases, 10-12 but fever alone does not distinguish this virus from other infections. 13 Therefore, absence of fever is inadequate for travel screening and likely for other decision thresholds such as whether ED staff can work shifts. 14 Hyposmia (diminished sense of smell) and hypogeusia (diminished taste) have also emerged as COVID-19 symptoms. Both hyposmia (positive likelihood ratio [LR+] 5.3, negative likelihood ratio [LR-] 0.61) and hypogeusia (LR+ 7.1, LR-0.38) are better to rule-in than to rule-out COVID-19, but neither may be fully adequate for either purpose. 15 Although multiple COVID-19 studies report acute smell or taste disorders as a distinguishing symptom, no other studies report diagnostic accuracy or sufficient details to compute likelihood ratios for hyposmia or hypogeusia. [16] [17] [18] [19] [20] [21] Loss of smell is not necessarily associated with nasal obstruction or rhinorrhea. 22 In one case-control study, new onset smell and taste disorders are more common with COVID-19 than with influenza (39% vs. 13%). 16 Consequently, influenza decision

This article is protected by copyright. All rights reserved aids or diagnostic algorithms do not incorporate hyposmia or hypogeusia. 23,24 Anosmia, which may be the only complaint in some COVID patients, 25 is noted by 47%-73% of COVID-19 patients and is the initial symptom in 27%. [18] [19] [20] Additionally, 71% recall an acute onset of symptoms associated with taste and smell. 16 Anosmia is more common in women and may persist for two weeks. 17 Predictive models incorporating a change in taste or smell to distinguish COVID-19 from viral mimics appear most sensitive. 26 Cough is only present in 58% patients. 10, 12 Neither cough, dyspnea, sore throat, nor fatigue distinguish COVID-19 from other illnesses, 13 but current studies do not quantify accuracy. 12,27

Lymphopenia occurs in over 50% of COVID-19 patients. 10, 11, 28 Neutrophil to lymphocyte and platelet to lymphocyte ratios do not distinguish Elevated LDH is also frequently described. 10, 28, 30, 31 None of these lab findings are commonly utilized in the diagnosis of influenza, but their prevalence and accuracy to distinguish COVID-19 from other viral mimics merit further evaluation. 23,24 Elevated Prothrombin Time (PT), ferritin, D-dimer or IL-6 are associated with severe COVID-19. 31-33 Existing studies do not report sensitivity or specificity of these labs.

Most studies use rRT-PCR as the criterion standard for diagnosing COVID-19. This test as used in current assays provides a qualitative detection of nucleic acid from the SARS-CoV-2 virus. 

This article is protected by copyright. All rights reserved capacity and time-to-diagnosis in many settings, 34,35 prompting laboratory researchers to explore the concept of specimen pooling in which multiple patients' samples are tested simultaneously with further individual testing only if the pooled specimen is positive. 36 The optimal pool specimen when COVID-19 community prevalence is less than 10% is four patients, which improves testing efficiency by 69%. 37 There is limited information on the diagnostic accuracy of the rRT-PCR test. Although an increasing number of studies provide head-to-head comparisons, 38-40 systematic reviews provide little quantitative accuracy data and no meta-analysis or assessment of individual study quality. 41 No rRT-PCR test is clearly superior to others in terms of diagnostic accuracy, but some provide faster results and commercial tests may be less sensitive than hospital-developed tests. 40,42 It is known, however, that false negatives are frequent, so current recommendations advise incorporating patient's exposure risk, clinical signs and symptoms, routine lab and imaging findings, serology, and (when available) CT results into real-time determination of COVID-19 status. Repeat or even serial rRT-PCR testing is required to confidently exclude COVID-19. Multiple studies report initially negative rRT-PCR results becoming positive with subsequent rRT-PCR tests in the following days or weeks. 43,44 Others report hospitalized COVID-19 patients with initially positive rRT-PCR tests becoming negative prior to discharge with subsequent readmission for positive tests in the ensuing days. 45 Ren et al. noted rRT-PCR sensitivity with one test was 78% and increased to 86% with a second test. 46 A strategy of three negative rRT-PCR results is superior to two negative rRT-PCR followed by bronchoalveolar lavage. 47 Repeating initially negative rRT-PCR up to five times increases sensitivity to 98%. 48 COVID-19 patients identified on first rRT-PCR often have more severe disease associated with higher mortality, likely due to higher quantities of virus in those individuals. 48 Older patients are more likely to remain rRT-PCR positive for an extended period, but whether this means they are contagious has yet to be determined. 44 Potential reasons for false negative rRT-PCR results are summarized in Table 1 . 49-51 Emergency physicians will rely upon the rRT-PCR assay selected by their hospital laboratory, which may

This article is protected by copyright. All rights reserved balance the limit of detection and sensitivity against turn-around-time, complexity, cost, workflow, availability of reagents and kits, specimen type, and lab personnel risk handling those specimens. 52 Patients under investigation for COVID-19 who ultimately rule-out are rarely reported in currently available studies, so specificity and false positives are generally not reported in the literature. However, false positives appear rare. 53 In CDC testing, there was no significant cross-reactivity with other common respiratory viruses or seasonal coronaviruses. 54 Contamination of the specimen or reagents used in the rRT-PCR is therefore the main mechanism for false positives results. The CDC recommends protocols to prevent and detect potential contamination in order to minimize false positive results. 49, 54 Nasopharyngeal (NP) samples are most commonly obtained and studied, but oropharyngeal (OP), saliva, sputum, stool, blood, and/or urine specimens can also be evaluated. Obtaining NP samples requires time and appropriate training, increases exposure to staff secondary to coughing and gagging, and is uncomfortable for patients. Methodologically, few rRT-PCR accuracy studies describe how research or clinical staff were trained to collect NP specimens, so fidelity and reproducibility remain in question. 55 Wang et al provide videos describing NP and OP collection methods, note poor agreement between the two sampling methods (kappa = 0.31), and a higher yield with NP. 56 Saliva can be collected outside the hospital without training, perhaps as part of a telemedicine evaluation for COVID-19. 57,58 One small Italian study indicated that saliva specimens demonstrate detectable SARS-Co-V-2 virus and the limit of detection is not affected by patient age. 59 Sputum samples exhibit higher viral load than OP sites. 60-62 However, as already noted many patients under investigation lack a cough and fewer still have sputum production. Expectoration of sputum may also expose health care workers collecting the sample to aerosols that would not have been generated without a sample collection attempt. Furthermore, a Bayesian analysis of prevalence-dependent positive and negative predictive values by Ghosal and Sinha demonstrates that even when the COVID-19 prevalence is high (54%) the positive predictive value (PPV) of sputum rRT-PCR is only 95.7% and the negative predictive value (NPV) is 52%. 63 PPV and NPV vary with disease prevalence.

Specifically, PPV increases with higher disease prevalence and NPV increases with lower disease Accepted Article prevalence making extrapolation to clinical populations challenging if the study prevalence does not match the patients to whom the test is applied. 64 For this reason, diagnosticians prefer likelihood ratios. 65 Blood and urine are inadequate specimens for rRT-PCR as most patients do not exhibit virus in these body fluid compartments. 66 In addition to the CDC developed rRT-PCR test, manufacturers have developed molecular tests that target different portions of the SARS-CoV-2 viral genome and run on rapid testing platforms. For example, reverse transcription loop mediated isothermal amplification (RT-LAMP) can detect SARS-CoV-2 within 30 minutes. [67] [68] [69] Other laboratories are exploring highthroughput sequencing as for inconclusive fluorescence quantitative polymerase chain reaction specimens as a rapid mediator for the presence or absence of SARS-CoV-2. 70 The diagnostic accuracy of these tests is similarly not reported, but these tests have not shown cross-reactivity to other respiratory viruses and bacteria.

On May 8, 2020, the US FDA issued an EUA for a SARS-CoV-2 antigen test. 71 This test detects SARS-Co-V or SAVS-CoV-2 nucleocapsid protein antigens in NP or nasal specimens using a lateral flow immunofluorescent sandwich assay. 71 This assay is run on a point-of-care device in laboratories that are able to perform high, moderate, or waived complexity tests, and can provide tests within minutes. 72 While the diagnostic accuracy of this test is not available at this time, the FDA reports high specificity but sensitivity that is less than rRT-PCR. The FDA and the manufacturer recommend negative results "be treated as presumptive and confirmed with a molecular assay, if necessary for patient management". 73 Chest X-ray Chest x-ray is essential to evaluate for COVID-19 mimics such as pneumonia, pleural effusion, or pulmonary edema. Typical COVID-19 findings include hazy opacities that are often bilateral and peripheral. 74 With the exception of one outlier, the reported sensitivity of single view chest xray for COVID-19 ranges from 33% to 60%. 75 

This article is protected by copyright. All rights reserved accuracy of chest x-ray early in the COVID-19 pandemic. 80 Currently available COVID-19 chest

x-ray studies do not report specificity or reliability. 75 

Computed tomography (CT) findings suggesting COVID-19 include ground glass opacity (often bilateral) and peripheral predominant lesions without mediastinal adenopathy or pleural effusions, though these findings represent non-specific manifestations of acute lung injury associated with numerous infectious and non-infectious etiologies. 81, 82 Incidental findings consistent with COVID-19 are observed on CT of the chest in patients without respiratory symptoms. 83 Multiple studies report COVID-19 identified by CT after one or more negative rRT-PCR tests. [84] [85] [86] [87] When the COVID-19 epidemic erupted in China, clinicians lacked access to rRT-PCR kits and then as rRT-PCR became available, low rRT-PCR sensitivity reinforced belief in the additive value of CT for many. 88 These observations and scenarios prompted some to advocate for CT as a first-line supplement to the diagnostic evaluation for COVID-19, combining rRT-PCR with CT. 89, 90 If CT alone or in combination with rRT-PCR reduced false-negative rates, the positive public health implications for case identification and control of disease transmission could be substantial. However, these benefits must be balanced against the cost of CT, medical radiation dangers, or practical limitations in busy hospitals with hourly trauma and stroke arrivals and potentially time-dependent emergencies juxtaposed against advised CT shutdowns for COVID-19 cleaning requiring 30 or more minutes. 91, 92 This cleaning time would also delay access to CT for every patient in the ED, thereby prolonging potential exposure to those in the ED to other patients with COVID-19. 92 Some propose COVID-19 patients wear N-95 masks and plastic bags over their heads to eliminate or reduce these cleaning times. 27 Pragmatically, among those detected by CT no defined benefit, such as reduced mortality or faster resolution of COVID-19 symptoms has been described. 93 In addition, radiologists' sensitivity for diagnosing COVID-19 by CT findings ranges from 72% to 94% with specificity from 24% to 100%. 94 Preliminary artificial intelligence studies report radiologists' sensitivity improves from 79% to 88% and specificity

This article is protected by copyright. All rights reserved from 88% to 91% with this artificial intelligence image augmentation, 95 while others hypothesize that the most valuable role for this technology may be quantify the proportion of lung affected by COVID-19. 96 Despite these issues, multiple studies highlight that the sensitivity of CT is substantially higher than that of the first rRT-PCR, while combining CT and rRT-PCR provides maximal sensitivity (~97%). 89, 97, 98 Theoretically, the sensitivity of CT would decline when testing populations outside of an epidemic (low prevalence rates), while specificity would be reduced when mimics like influenza are more common. 9, 27 The British Society of Thoracic Imaging recommends against CT when rRT-PCR is positive, but to consider CT when the initial rRT-PCR is negative in order to identify co-existing disease or potential COVID-19 complications such as pulmonary embolism. 99 Tavare et al. developed a single-center protocol to prioritize inpatient CT decision-making for initial COVID-19 negative rRT-PCR patients based upon initial clinical suspicion and chest x-ray findings. 100 

The US FDA has also issued an EUA for the development of SARS-CoV-2 antibody tests. These antibody tests detect circulating IgM, IgG or both that are reactive against SARS-CoV-2 virus using lateral flow assays (LFA) or enzyme-linked immunosorbent assay (ELISA). 2 However, unlike rRT-PCR tests, there is data regarding the diagnostic accuracy of these serologic tests.

Whitman and colleagues evaluated 10 LFA and 2 ELISA tests for SARS-CoV2 antibodies. 101 They used plasma or serum samples from patients with symptomatic, rRT-PCR-confirmed positive patients as the gold standard for disease, and pre-COVID-19 specimens from the American Red Cross as negative controls. Sensitivity of both IgM and IgG varied by days since symptoms onset, with sensitivities for either IgM or IgG at >20 days ranging from 82% to 100%. Specificity for either IgM or IgG also varied by test, ranging from 87% to 100%. 101 Similarly, Benavid and colleagues used a commercially available LFA test to perform a seroprevalence study in Santa Clara county, California and reported a sensitivity of 80% and a specificity of 99.5%. 102

True positive serologic tests for SARS-CoV-2 antibodies indicate prior infection with SARS-CoV2 and the development of an immune response. This may be helpful in identifying those who

This article is protected by copyright. All rights reserved were asymptomatic or minimally symptomatic at the time of infection, as well as those who were unable to receive a molecular test when symptomatic. While some experts believe that the presence of IgM or IgG reactive against SARS-CoV-2 will confer immunity, 103 this has not yet been shown. 104 If the presence of antibodies on a true positive serologic test does confer immunity, the titer of antibodies required to confer immunity remains unknown, as does the duration of that immunity.

False positive results may be due to cross-reactivity with other coronavirus strains which cause the common cold. The FDA recommends the following information be included in the instructions for use and patient test reports:

Knowledge of the diagnostic characteristics, including sensitivity, specificity, and likelihood ratios of tests for SARS-CoV2, the virus that causes COVID-19, is important to understand how to best apply these tests for patient care and disease surveillance. Because this novel virus emerged as a significant pathogen in humans only a few months ago, diagnostic tests have been developed rapidly under FDA EUAs in the US. Consequently, we have less information about the diagnostic accuracy of these tests than we would under normal circumstances, but we do know that both false negatives and false positives may occur. An illustration of the false positive and false negative rate as a function of prevalence for two serologic tests for SARS-CoV-2 is provided in Figure 3 .

False negative tests commonly occur with rRT-PCR tests for several reasons (Table 1 ). There are a number of potential implications of a false negative rRT-PCR test for SARS-CoV-2. From the

This article is protected by copyright. All rights reserved patient's standpoint, a patient with a negative test may lead to an assumption that they are not infected and subsequently diminished adherence to instructions to isolate and take other infection control measures, increasing the risk of infecting others. In the hospital setting, precautions may be relaxed in the presence of a negative test, increasing the risk of transmission to healthcare workers and other patients. In patients with moderate or high pretest probability of disease, a negative test may not reduce the posttest probability of disease below a level where precautions to prevent spread of disease become less necessary.

In patients with a low pretest probability of disease, the likelihood of disease given a negative test will be low. However, even low individual likelihoods of disease can cumulatively contribute to substantial risk of outbreaks across larger groups for more contagious infectious diseases, such as COVID-19.

False negative tests are also a consideration with serological testing. However, since these tests should generally not be used to assess an active infection, the risks of a false negative are less significant for disease transmission. A false negative serological test would incorrectly classify a person as not having an immune response to SARS-CoV-2. If "immunity passports" became a reality, this could incorrectly and adversely affect a person's ability to travel or work. 104 

The increased sensitivity of CT for COVID-19 might provide a net public health benefit if falsenegative rRT-PCR patients with higher clinical suspicion were accurately identified during the initial ED evaluation. Mathematical models provide a theoretical basis for the concept that increasing diagnostic efficiencies (for example, by improving sensitivity with addition of CT) will decrease the risk of COVID-19 transmission. 106 Pending the availability of rapid, reliable, and sufficiently accurate COVID-19 tests in ED settings, the Identify-Isolate-Inform (3I) approach to decrease spread might be improved with more liberal CT use. 107 One Italian hospital reported liberal CT screening for respiratory patients with possible false-negative chest x-ray results, but thus far has not reported on the positive or negative impact of that approach on individual patient care or public health. 108 In the early stages of COVID-19, as many as 50% of patients

This article is protected by copyright. All rights reserved with respiratory symptoms may have normal imaging. 96 Radiologists have also noted that the quality of early CT accuracy studies is questionable because the rRT-PCR assay used as the criterion standard is either not described or the accuracy of that standard undefined. 82 In addition, CT findings are not pathognomonic for COVID-19 as influenza, cytomegalovirus, and atypical pneumonia have similar findings. 96, 109 As a consequence of these CT limitations in addition to the costs, radiation exposure, and downstream effect on other patients in terms of diagnostic delays and cross-contamination, multiple groups, including the Fleischner Society and the British Society of Thoracic Imaging discourage CT as a routine screening approach. 99, 110 Nonetheless, CT likely plays a role when rRT-PCR tests are either too inaccurate, unavailable or suffer unacceptably slow turnaround times in patients with higher levels of COVID-19 concern based on exposure history or other clinical findings. 74 The public health benefits of a more liberal CT screening approach from the ED merit additional research.

False positive tests associated with rRT-PCR for SARS-CoV2 are believed to be rare and would most commonly occur due to contamination. False positive tests may occur more commonly with serological tests, which have reported specificities ranging from 87-100%. 101 The positive predictive value is a function of both test sensitivity and specificity as well as the pretest probability of disease. This implies that positive test results are more likely to represent false positive results when the pretest probability of disease is low. 111 The instability of positive predictive value is especially important as we apply imperfect diagnostic tests to low risk patient populations, such as asymptomatic patients in low prevalence communities. As an example, the antibody test used in a California community study has a reported sensitivity of 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved society with a false positive serologic test for SARS-CoV2 antibodies. Patients may assume that they have developed immunity to COVID-19, leading to a reduction in risk-mitigating activities such as physical distancing. Healthcare workers with false positive tests may similarly reduce their vigilance and use of precautions due to an incorrect assumption that they have immunity.

This could place these individuals and their close contacts at increased risk of contracting COVID-19.

Multiple forms of diagnostic bias exist and each skew measured estimates of sensitivity and specificity in different directions. 112 Incorporation bias is possible when the criterion standard includes the index test (for example, rRT-PCR) in ultimately determining whether the disease is present or absent. Incorporation bias increases measured sensitivity and specificity. This is pertinent to COVID-19 because most early studies incorporate rRT-PCR into the criterion standard. 9,113 Differential verification bias is possible when patients with a positive or concerning index test (e.g., CT findings associated with COVID-19) are more likely to receive an immediate invasive gold standard such as repeat rRT-PCR testing or bronchoalveolar lavage specimens. 82, 97 Differential verification bias raises specificity in diseases that resolve spontaneously or lowers specificity for diseases that only become detectable during follow-up. 9 Imperfect gold standard bias is possible when the standard used to classify the presence or absence of disease misclassifies some patients. Imperfect gold standard bias raises observed specificity if errors on the index test and "copper standard" are correlated with true disease status and lowers observed specificity if errors on the index test and the copper standard are independent. 9 This is pertinent to COVID-19 because no well-accepted criterion standard yet exists. A better criterion standard for COVID-19 will certainly emerge and we propose some ideas in Table 2 . 114, 115 Temporal bias reflects variation in observed accuracy based on the period of time or stage of disease when index testing occurred. 116 In COVID-19 viral shedding is highest in the early stages of disease with the highest positive rates noted within the first week. 117, 118 Spectrum bias is possible when the spectrum of disease severity differs between the study and clinical application (example, critically ill COVID-19 patients in the Intensive Care Unit versus

This article is protected by copyright. All rights reserved asymptomatic patients evaluated in ambulatory clinics). Spectrum bias skews observed sensitivity upwards in sicker populations and skews specificity upward in healthier patients. 9, 119 Spectrum bias is worth considering when applying diagnostic accuracy results from patients with varying severity of illness to dissimilar populations. For example, among COVID-19 patients from cruise ships evaluated with CT, those with symptoms more commonly had COVID-19 CT findings than those without symptoms (80% vs. 40%). 120

The rapidly expanding evidence base around COVID-19 diagnostic accuracy for clinical exam, routine labs, imaging, and advanced testing provides important lessons moving forward for clinicians, researchers, and journal reviewers. COVID-19 researchers need to contemplate myriad biases carefully in reporting observed diagnostic accuracy. If a bias is likely and the anticipated skew in observed sensitivity or specificity is upwards and the observed accuracy is already too low, further studies of that diagnostic test may not be warranted. The STARD reporting guidelines provide manuscript protocols to ensure adequate description of methods and results so that diagnostic biases are easier to identify. 7, 8 Unfortunately, none of the early COVID-19 diagnostic research cites STARD or adheres to these reporting standards, which is not uncommon in emergency medicine. 121, 122 Clinical decision aids consist of three or more findings on history, physical exam, routine labs, or imaging that, in combination, more accurately identify patients at lower or higher risk of a disease or outcome. Diagnostic and prognostic decision aids are commonly developed and employed in emergency medicine to reduce practice variability without compromising patient outcomes. 123 Efforts to develop COVID-19 decision aids might include something like the Pulmonary Embolism Rule-Out Criteria (PERC) rule to identify subsets of ED patients at lower risk of COVID-19 pending definitive testing. 124 Alternatively, a decision aid might serve prognostic purposes to identify COVID-19 patients more likely to decompensate in response to the viral infection. [125] [126] [127] [128] When decision aid investigators attempt to derive and validate these

This article is protected by copyright. All rights reserved instruments, higher quality emergency medicine research quantifying accuracy and reliability (or the elements of history, physical exam, labs, and imaging that become predictor variables of the decision aid) will be required as the basis for selecting variables likely to improve model performance.

Most laboratory tests are quantitative rather than qualitative, including COVID-19 rRT-PCR and serological assays. When sensitivity and specificity are reported, the quantitative labs have been dichotomized at some level. Another approach to evaluating diagnostic accuracy for quantitative data is interval likelihood ratios (iLR). 129 One advantage of iLR's is that indeterminant results are more readily interpreted. As COVID-19 diagnosticians identify the rRT-PCR and serological tests that best balance availability, accuracy, reliability, and cost, reporting iLR's could provide added value for clinicians.

Ultimately, ED physicians' clinical impressions concerning the presence or absence of COVID-19 are communicated to patients and families -usually without access to definitive testing.

Patient communication tools to convey the basics of COVID-19 personal protection and infection prevention exist, 130,131 but shared decision-making instruments that communicate the uncertainties of clinical exam, imaging, and even rRT-PCR do not exist. Figure 4 provides one example of a Cates Plot that could be used to communicate the accuracy limitations of rRT-PCR based on current evidence. Actual shared decision-making instruments will require scientific investigation using accepted methodology before widespread implementation. 132 

This scoping review has several limitations. The pace of publications around COVID-19 and diagnostics in the first half of 2020 has been astonishing. At best, this review will serve as a snapshot in time, although hopefully illuminating issues that require higher methodological standards and peer-review attention moving forward. Due to time constraints the search strategy was limited to English language and published research. More research undoubtedly exists in the gray literature. Since earlier systematic reviews exploring aspects of COVID-19

This article is protected by copyright. All rights reserved diagnostic testing did not identify or report additional measures of sensitivity, specificity, or likelihood ratios for hyposmia, hypogeusia, or rRT-PCR, we are confident that this search presents a complete scoping review of current knowledge. 10, 133 Others have also noted the absence of diagnostic accuracy reporting amidst the flurry of COVID-19 publications. 134, 135 Additionally, this scoping review does not focus on special emergency medicine populations such as pediatrics, geriatrics, or obstetrics because other reviews already exist for these patients. 136, 137 Most importantly, we report no formal assessment of study quality using accepted instruments such as the QUADAS-2, 138 although informal assessment of published research to date suggests limited adherence to the full set of recommended methodological standards for studies of diagnostic test performance.

Clinicians should be aware of the current limited knowledge around history, physical exam, labs, and imaging for COVID-19. Fever and acute onset disorders of taste and/or smell are the most common findings on history and physical exam associated with COVID-19. Lymphopenia is associated with COVID-19 diagnosis, while elevated LDH and PT are associated with severe disease. rRT-PCR has emerged as the primary diagnostic test for suspected COVID-19, but access has been limited, diagnostic accuracy is under-reported, and between-assay comparative accuracy is rarely evaluated. However, typical testing algorithms and diagnostic accuracy studies rely heavily on rRT-PCR results with frequent false negatives. Chest CT is indicated for equivocal cases or when considering diagnoses like pulmonary embolism, but is not recommended as a general screening protocol. In cases with high clinical suspicions, repeat rRT-PCR testing with or without CT scanning may be beneficial to reduce community spread.

Antigen tests have only recently been approved, and diagnostic accuracy information is similarly limited. Serology may identify past COVID-19 exposure, but the role of antibody testing and implications for ED decision-making remain undefined. Current clinical, imaging, and laboratory studies neglect diagnostic accuracy reporting standards and likely suffer from various biases.

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Accepted Article This article is protected by copyright. All rights reserved 79

Imaging Profile of the COVID-19 Infection: Radiologic Findings and Literature Review. Radiology: Cardiothoracid Imaging

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Diagnostic performance of chest CT to differentiate COVID-19 pneumonia in non-high-epidemic area in Japan

A Critical Review of the Literature to Date

Incidentally Diagnosed COVID-19 Infection in Trauma Patients; a Clinical Experience

Clinical features of atypical 2019 novel coronavirus pneumonia with an initially negative RT-PCR assay

Use of chest CT in combination with negative RT-PCR assay for the 2019 novel coronavirus but high clinical suspicion

Chest CT for Typical 2019-nCoV Pneumonia: Relationship to Negative RT-PCR Testing

Computed Tomographic Imaging of 3 Patients With Coronavirus Disease 2019 Pneumonia With Negative Virus Real-time Reverse-Transcription Polymerase Chain Reaction Test. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

CT screening for early diagnosis of SARS-CoV-2 infection -Authors' reply. The Lancet Infectious diseases

Accepted Article This article is protected by copyright. All rights reserved 89

A diagnostic model for coronavirus disease 2019 (COVID-19) based on radiological semantic and clinical features: a multi-center study

A case report of COVID-19 with false negative RT-PCR test: necessity of chest CT

Diagnosis of SARS-CoV-2 Infection based on CT scan vs. RT-PCR: Reflecting on Experience from MERS-CoV. The Journal of hospital infection

Chest CT in patients suspected of COVID-19 infection: A reliable alternative for RT-PCR

CT screening for early diagnosis of SARS-CoV-2 infection. The Lancet Infectious diseases

Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT

AI Augmentation of Radiologist Performance in Distinguishing COVID-19 from Pneumonia of

Cautions about radiologic diagnosis of COVID-19 infection driven by artificial intelligence. The Lancet Digital Health

Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR

Diagnosis of the Coronavirus disease (COVID-19): rRT-PCR or CT?

A British Society of Thoracic Imaging statement: considerations in designing local imaging diagnostic algorithms for the COVID-19 pandemic

Managing high clinical suspicion COVID-19 inpatients with negative RT-PCR: A pragmatic and limited role for thoracic CT

Test performance evaluation of SARS-CoV-02 serological assays

COVID-19 antibody seroprevalence in

The promise and perils of antibody testing for COVID-19

Immunity passports" in the context of COVID-19. World Health Organization

FDA: Policy for Coronavirus Disease-2019Tests During the Public Health Emergency

Effect of delay in diagnosis on transmission of COVID-19

2019-nCoV: The Identify-Isolate-Inform (3I) Tool Applied to a Novel Emerging Coronavirus. The western journal of emergency medicine

Radiology Department Preparedness for COVID-19: Facing an Unexpected Outbreak of the Disease

Clinical and imaging features of COVID-19

The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society

Evidence-based emergency medicine/editorial. The problem with sensitivity and specificity

CDC. FACT SHEET FOR HEALTHCARE PROVIDERS CDC -2019-nCoV Real-Time RT-PCR Diagnostic Centers for Disease Control

Partial verification bias and incorporation bias affected accuracy estimates of diagnostic studies for biomarkers that were part of an existing composite gold standard

Multiple parameters required for diagnosis of COVID-19 in clinical practice

When should a new test become the current reference standard?

Evidence-Based Emergency Care: Diagnostic Testing and Clinical Decision Rules

Profile of RT-PCR for SARS-CoV-2: a preliminary study from 56 COVID-19 patients

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Variation of a test's sensitivity and specificity with disease prevalence

Chest CT findings in cases from the cruise ship "Diamond Princess

Adherence to Standards for Reporting Diagnostic Accuracy in Emergency Medicine Research

Overcoming the Tower of Babel in Medical Science by Finding the "EQUATOR": Research Reporting Guidelines

Doing Research in Emergency and Acute Care: Making Order Out of Chaos

Accepted Article This article is protected by copyright. All rights reserved

Prospective multicenter evaluation of the pulmonary embolism rule-out criteria

Prediction models for diagnosis and prognosis of covid-19 infection: systematic review and critical appraisal

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

A Tool to Early Predict Severe Corona Virus Disease 2019 (COVID-19) : A Multicenter Study using the Risk Nomogram in Wuhan and Guangdong, China. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Comparing rapid scoring systems in mortality prediction of critical ill patients with novel coronavirus disease. Academic Emergency Medicine

Interval likelihood ratios: another advantage for the evidence-based diagnostician

Stopping the Spread of

Masks and Coronavirus Disease

State of the Science: Tools and Measurement for Shared Decision Making

COVID-19 diagnosis and management: a comprehensive review

Incorporating Test Characteristics Into SARS-CoV-2 Testing Policy-Sense and Sensitivity. JAMA Health Forum Web site

All rights reserved 135. Bachelet VC. Do we know the diagnostic properties of the tests used in COVID-19? A rapid review of recently published literature

A systematic scoping review of COVID-19 during pregnancy and childbirth

COVID-19 in older adults: Key points for emergency department providers. Geriatric Emergency Department Collaborative

QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies

Accepted Article Covid-19

COVID-19 diagnostic testing

COVID-19 serotherapy

Covid-19" OR epidem*[tiab] OR epidemic* OR epidemy OR new[tiab] OR "novel"[tiab] OR "outbreak" OR pandem* OR "SARS-CoV-2" OR "Shanghai" OR "Wuhan") AND ("Coronavirus Infections

Sensitivity and Specificity"[MeSH] OR "Point-of-Care Testing

OR "next generation sequencing"[tiab] OR "point-of-care test"[tiab] OR "point of care tests

2019-nCoV' OR '2019nCoV' OR 'cov 2' OR 'Covid-19' OR 'sars coronavirus 2' OR 'sars cov 2' OR 'SARS-CoV-2' OR 'severe acute respiratory Accepted Article This article is protected by copyright. All rights reserved syndrome coronavirus 2' OR 'coronavirus 2' OR 'COVID 19' OR 'COVID-19' OR '2019 ncov' OR '2019nCoV' OR 'corona virus disease 2019' OR 'cov2' OR 'COVID-19' OR 'COVID19' OR 'nCov 2019' OR 'nCoV' OR 'new corona virus' OR 'new coronaviruses' OR 'novel corona virus' OR 'novel coronaviruses' OR 'SARS Coronavirus 2' OR 'SARS2' OR 'SARS-COV-2' OR 'Severe Acute Respiratory Syndrome Coronavirus 2'):ti,ab,kw OR ((19 OR 2019 OR '2019-nCoV' OR 'Beijing' OR 'China' OR 'Covid-19' OR epidem* OR epidemic* OR epidemy OR new OR 'novel' OR 'outbreak' OR pandem* OR 'SARS-CoV-2' OR 'Shanghai' OR 'Wuhan'):ti,ab,kw AND

Polymerase Chain Reaction'/exp OR 'reverse transcription polymerase chain reaction'/exp OR 'high throughput sequencing'/exp OR 'sensitivity and specificity'/exp OR 'point of care testing'/exp OR 'Antigen'/exp OR 'Serology'/exp OR 'immunoglobulin G'/exp OR 'immunoglobulin M'/exp OR 'Clustered Regularly Interspaced Short Palindromic Repeat'/exp OR 'CRISPR Cas system'/exp OR 'differential Diagnosis'/exp OR pcr:ti,ab,kw,de OR 'digital droplet':ti,ab,kw,de OR 'next generation sequencing':ti,ab,kw,de OR 'point-of-care test':ti,ab,kw,de OR 'point of care tests':ti,ab,kw,de OR antigen:ti,ab,kw,de OR analyte:ti,ab,kw,de OR serology