key: cord-0900245-6tlkpmw6 authors: Sultan, Shahnaz; Siddique, Shazia M.; Altayar, Osama; Caliendo, Angela M.; Davitkov, Perica; Feuerstein, Joseph D.; Francis, Dawn; Inadomi, John; Lim, Joseph K.; Falck-Ytter, Yngve; Mustafa, Reem A. title: AGA Institute Rapid Review and Recommendations on the Role of Pre-Procedure SARS-CoV2 Testing and Endoscopy date: 2020-07-28 journal: Gastroenterology DOI: 10.1053/j.gastro.2020.07.043 sha: d2ddfce8260e3da0a4be2c0c401977e04ace0a53 doc_id: 900245 cord_uid: 6tlkpmw6 nan The genome of the SARS-CoV2 virus, the cause of COVID-19, was first identified on January 12, 2020. This was a critical first step that allowed for the development of molecular diagnostic tests to identify the presence of virus. 1-3 At the individual patient level, testing for SARS-CoV-2 infection in symptomatic patients helps to identify individuals who can be isolated to prevent the spread of disease and can inform treatment decisions aimed at reducing morbidity and mortality. 4 At the population level, widespread testing of individuals (symptomatic and asymptomatic) is critical to understanding the true prevalence of disease. This information can then inform local decisions regarding the economy and the provision of healthcare services, including the re-introduction of endoscopy across healthcare systems and ambulatory care centers. 5 Tests fall under two broad categories: tests that detect virus and tests that detect the presence of antibodies associated with the virus (serology tests). Direct detection of viral RNA is most commonly performed via nucleic acid amplification testing (NAAT) of specific known targets in the genome of the virus, using RT-PCR. 6 The most common sample types (or sources) are swabs that are taken from the nasopharynx and/or oropharynx, lower respiratory tract, or saliva by a trained healthcare worker or self-collection. It is important to recognize that the quality of sample collection, as well as the source, influence test results. Development of an antibody response to SARS-CoV-2 infection through the identification of antibodies indicates recent or past infection. The predictive value of a test refers to the probability of having a condition or disease in an individual with a positive test result (positive predictive value) and the probability of not having a condition or disease in an individual with a negative test result (negative predictive value). A pre-testing strategy in asymptomatic individuals prior to endoscopy may be informative in distinguishing people with SARS-CoV2 infection and those without SARS-CoV2 infection but it is affected by the prevalence of the disease in asymptomatic individuals. This rapid review and rapid guideline address the role of implementing a SARS-CoV2 pretesting strategy prior to endoscopy. A prior AGA guideline examined the role of PPE (including extended use and re-use of N95/N99 respirators or PAPRs in resource-constrained settings) when testing was not readily available; the aim of this guideline was to determine the role of testing in endoscopy re-opening. 7 To inform the recommendations, a systematic review of the diagnostic performance of currently available tests for SARS-CoV2 infection was conducted. A survey was conducted to provide information about the threshold of risk that endoscopists were willing to accept during endoscopy and an overview of strategies to estimate prevalence of infection among asymptomatic individuals is provided. Finally, the panel drafted recommendations for the role of a pre-testing strategy for low, intermediate, and high prevalence settings and a recommendation for serology testing (Table 1) . The strength of a recommendation is expressed as strong or conditional and has the following interpretation: Strong recommendation: • For clinicians: most individuals should follow the recommended course of action, and only a small proportion should not Conditional recommendation: • For clinicians: the majority of individuals in this situation would want the suggested course of action but many would not; different choices will be appropriate * These recommendations assume that all patients are systematically screened for COVID-19 symptoms using the CDC screening checklist and are required to wear masks while in the endoscopy unit. ** Appropriate PPE includes a face shield over the surgical mask and face shield over the N95/N99 respirator (to allow for re-use/extended use in limited PPE availability settings). We seek to provide an overview of the considerations of diagnostic testing in the decision to reopen or expand endoscopy operations in the setting of a pandemic. We summarize the available data on the diagnostic test characteristics of tests for SARS-CoV2 infection and provide evidence-based clinical guidance on the role of pre-testing prior to endoscopic procedures. This rapid review and guideline was commissioned and approved by the AGA Governing Board to provide timely, methodologically rigorous guidance on a topic of high clinical importance to the AGA members and the public. The guideline panel included gastroenterologists, an infectious disease expert, a member of the Practice Management and Economics Committee, and guideline methodologists from the Clinical Guideline Committee, and Clinical Practice Updates Committee. Panel members disclosed all potential conflicts of interest according to the AGA Institute policy. All members were required to disclose financial, intellectual or other potential conflicts. The target audience of these guidelines includes gastroenterologists, advanced practice providers, nurses, and other health care professionals in academic centers and in private practice settings across various geographic locations. Patients, as well as policy makers, may also benefit from these guidelines. These guidelines are not intended to impose a standard of care for individual institutions, healthcare systems or countries. They provide the basis for rational informed decisions for clinicians, patients and other health care professionals in the setting of a pandemic. This rapid guideline is intended to help clinicians make decisions about pre-procedural testing prior to endoscopy however decisions may be constrained by local health system or state-level policies as well as availability of resources, specifically RT-PCR tests and PPE. Recommendations are accompanied by qualifying remarks which serve to facilitate more accurate implementation. They should never be omitted when recommendations from these guidelines are quoted or translated. A summary of the recommendations is provided in Table 1 with a more detailed rationale for each recommendation in the discussion section. The implementation considerations section in this guideline will help clinicians implement these recommendations. This section includes a checklist for endoscopy re-opening, instructions for an online interactive tool, and a matrix to facilitate pre-testing strategy considerations in low and high prevalence areas accounting for testing and PPE availability The evidence base to support this recommendation included (1) a systematic review and metaanalysis of the diagnostic test performance (sensitivity and specificity) of currently available tests in the U.S. (2) a survey of gastroenterologists to understand the acceptable threshold of risk and (3) Two reviewers were assigned to each database (SMS and PD to SSRN, OA and JF to Medrxiv and Biorxiv, SS and RM to LitCovid) and independently screened titles and abstracts, as well as eligible full-text studies. Disagreements were resolved by discussion to reach consensus. Studies were included if they reported data on diagnostic test accuracy (cohort studies, cross sectional studies and case-control studies). All studies compared an index test to a reference "gold standard" test. Reviewers extracted relevant information into a standardized data extraction form (Supplement Table 1 ). Data extracted included study characteristics (authors, publication year, country, study design), index test and reference standard, and sensitivity and specificity of the index test. Additionally, studies that reported on prevalence of SARS-CoV2 infection were also identified and reviewed. Risk of bias for studies on diagnostic test accuracy was assessed utilizing the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 revised tool. 9 This tool assesses the risk of bias in four domains: patient selection, index test, reference standard, and flow and timing of study. Studies were categorized as having higher quality if: a) they had a crosssectional or cohort design, as opposed to case-control design, b) included a reference standard that is not a laboratory-developed test (LDT), and c) if there were two reference standards or at least 1 reference standard with a second test for discordant results. We used the bivariate normal model to pool sensitivity and specificity using the logit transformation. 10 We performed sensitivity analyses by limiting the analysis to studies at low risk of bias based on the patient selection and reference test domains of the QUADAS-2 tool. We used the package mada version 0.5.8 in R version 3.6.3 to conduct the analysis and produce the forest plots. 11, 12 The GRADE framework was used to assess overall certainty by evaluating the evidence for each outcome on the following domains: risk of bias, imprecision, inconsistency, indirectness, and publication bias. 13, 14 The GRADE interactive summary of findings table was generated using the GRADEpro Guideline Development Tool. 15 In developing recommendations, the panel considered the certainty of evidence, the balance between the desirable and undesirable effects (i.e. the benefits and downsides of a pre-testing strategy) and additional domains were acknowledged where applicable (e.g., feasibility, resource use, acceptability). For all recommendations, the expert panelists reached consensus. As per GRADE methodology, recommendations are labeled as "strong" or "conditional". See Supplement Tables 2 and 3. The words "we recommend" indicate strong recommendations and "we suggest" indicate conditional recommendations. Guideline panels often conduct internal surveys amongst panel members to determine values and preferences of providers. In order to gain a better understanding of a broader population of endoscopists, the panel developed a survey open to all AGA members. The goal was to understand the threshold of endoscopists to accept risks associated with pre-testing to inform PPE use (surgical mask versus N95/N99 or PAPR). We developed a short online survey that was piloted and modified prior to dissemination. Prior data has shown that endoscopy centers in North America are adopting pre-testing strategies. 16 The purpose of our survey was to further understand risk aversion thresholds, based on false negative results, that drive decision making for triage and PPE. A false negative result may provide false reassurance to an individual who has SARS-CoV2 infection, could be shedding virus, and may transmit the infection to others. The survey presented a clinical scenario of an asymptomatic patient undergoing elective endoscopy who tests negative for SARS-CoV2 72 hours prior to the endoscopy. Respondents were given five options for acceptable levels of risk of transmission of SARS-CoV2. The first option was 1/1000, with a comment stating that selecting this option would indicate willingness to open the endoscopy center using a surgical mask only. The last option was 1/40,000 with a comment stating that selecting that option would indicate willingness to open the endoscopy center only once N95s are available, despite a negative test result. The range of options were based off several assumptions: a) local prevalence of 1% (intermediate), b) baseline risk of SARS-CoV2 transmission without PPE of 50%, c) reduction of risk of COVID-19 transmission with PPE to 20% with surgical mask and 5% with N95 respirators. We collected responses from US-based gastroenterologists utilizing the "AGA Community" platform. The "AGA Community" is a non-public community for members of the American Gastroenterological Association through which gastroenterologists connect with colleagues and have conversations about relevant issues in their field. A pre-testing strategy in asymptomatic individuals prior to endoscopy can be informative in distinguishing people with SARS-CoV2 infection, and those without, but it is affected by the prevalence of the disease in asymptomatic individuals. To identify sources of data that provide information about the prevalence of infection in asymptomatic individuals we searched the published and unpublished literature and also reviewed public health websites. We also queried panel members regarding data from their local institutions. We identified 12 studies that provided information for 31 comparisons about test accuracy for the various NAAT tests. [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] The risk of bias was rated using the QUADAS-2 (See Supplement Table 4 ). The pooled sensitivity was 0.941 (95% CI: 0.908 -0.963) and pooled specificity was 0.971 (95% CI: 0.958 -0.980). We performed a sensitivity analysis for studies with low risk of bias and found similar results: pooled sensitivity 0.929 (95% CI: 0.847 -0.968) and pooled specificity 0.968 (95% CI: 0.942 -0.983). See Supplement Figure 2 . An important caveat of these studies is that tests were validated in samples from symptomatic individuals and it is likely that in asymptomatic individuals the tests may not perform as well and have lower sensitivity and specificity. We received 74 responses to the survey ( For diagnostic tests to inform decision-making, it is essential to determine the pre-test probability (e.g. prevalence) of disease in asymptomatic individuals. We searched for studies that evaluated the prevalence of SARS-CoV2 among asymptomatic individuals but only identified studies reporting on seroprevalence which were noninformative. Public websites reporting on numbers of positive cases (predominantly in symptomatic patients) and deaths were reviewed but due to limitations of non-random testing, variability in availability of testing, and delays in reporting, these estimates cannot directly inform prevalence estimates in asymptomatic individuals. Acknowledging the limited publicly available evidence for accurate estimates of prevalence of SARS-CoV2 infection in asymptomatic individuals, we relied on information from panel members' experiences within their health systems (based on rates of positive cases in asymptomatic individuals undergoing testing prior to any elective procedure) and modeling studies trying to estimate prevalence of SARS-CoV2 infection in the general population. We defined low prevalence areas as areas where the prevalence of asymptomatic infection is lower than 0.5%, intermediate prevalence areas as areas where the prevalence is between 0.5 and 2%, and high prevalence is greater than 2%. We defined hotspots as areas where there is a sudden surge in the number of daily cases with an acute burden on hospital capacity. The prevalence of exclusively asymptomatic infections is believed to be significantly lower than the commonly reported county or state estimates of positive cases and estimated to be approximately 1/10 th of the rates of positive cases. This is supported by a modelling study of state-level data which estimated that for each diagnosed symptomatic patient there may be 10 asymptomatic or undiagnosed individuals in that population. 29 Furthermore, based on a study conducted between April 13 and May 15, 2020 in Miami, the prevalence in an asymptomatic pre-endoscopy population was 0.25% compared to prevalence ranges from 5.4-12.7% in neighboring regions. 30 Similarly, another study at Stanford University found 2/999 total positives (0.2% prevalence). 31 The guideline panel acknowledges that local, state, and health system policies may dictate requirements for pre-procedural testing of asymptomatic patients as well as dictate decisions about PPE use. The following recommendations are based on the assumption that gastroenterologists have decision-making power over implementing a pre-testing strategy. Outcomes for decision-making: (i) triage and (ii) PPE use. A pre-testing strategy can inform endoscopy operations by helping with decisions regarding triage and PPE use. Using an estimate for the prevalence of asymptomatic SARS-CoV2 infection and test performance (sensitivity and specificity) one can calculate the number of true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN). All patients who test positive for SARS-CoV2 infection will have their elective procedure canceled and advised to self-quarantine for 14 days. A positive test result, however, includes asymptomatic individuals with SARS-CoV2 infection (TP) as well as individuals who test positive but do not have infection (FP). All patients who test negative for SARS-CoV2 infection can proceed with endoscopy and a surgical mask may be used by endoscopists and staff for upper and lower endoscopies. A negative test result, however, includes individuals who do not have infection (TN) and those individuals who have SARS-CoV2 infection but test negative (FN). The two main concerns with a pre-testing strategy are the false positives (i.e. individuals who test positive for SARS-CoV2 but do not have the infection) and false negatives (i.e. individuals who test negative for SARS-CoV2 but do have the infection). In a patient who tests negative for SARS-CoV2 infection (false negative) and a surgical mask is used for upper endoscopy, there may be a potential (albeit small) increased risk of infection to the endoscopy staff and false reassurance to the individual. In a patient who tests positive for SARS-CoV2 who does not have infection (false positive), implications for the patient include cancellation of the procedure, selfquarantine for 14 days, apprehension, and loss of work. Below we summarize the evidence, weigh the benefits and downsides and provide the rationale for each recommendation. Recommendation 1: For most endoscopy centers where the prevalence of asymptomatic SARS-CoV2 infection is intermediate and ranges from 0.5% to 2%, the AGA suggests implementing a pre-testing strategy using information about prevalence and test performance (sensitivity/specificity) in combination with considerations about the benefits and downsides of the strategy. -In settings where testing is feasible and there is less perceived burden on patients, and when the benefits outweigh the downsides (e.g. false positives do not significantly outnumber the true positives), an endoscopy center may reasonably choose to implement a pre-testing strategy. Among individuals that test negative, endoscopists and staff should use surgical masks** for all upper and lower endoscopies. Endoscopists and staff who are unwilling to accept the potential small risk of infection (from false negatives) may use N95/N99** respirator or PAPRs for upper and/or lower endoscopies. -In settings where the logistics of testing are challenging, and the downsides outweigh the benefits (e.g. the false positives outnumber the true positives) and endoscopy units are unwilling to accept the potential (albeit small) risk of infection then an endoscopy center may reasonably choose not to implement a pre-testing strategy and proceed with using higher PPE (N95/N99** respirators or PAPRs) for all procedures Summary of the Evidence We did not identify any comparative studies that directly assessed a strategy of pre-procedural testing versus no testing in asymptomatic individuals prior to endoscopy. The overall body of evidence was limited by small numbers, poorly defined and inconsistent reference standards, and test accuracy from case-controlled studies (which can lead to inflated estimates of test accuracy). Additionally, there was missing data in the studies regarding timing of specimen collection in relationship to onset of clinical symptoms and specimen type used for testing. Given all of these concerns, the overall certainty was low. Also, there were no test accuracy studies that evaluated the performance of RT-PCR tests in asymptomatic individuals. Based on evidence demonstrating similar viral shedding in presymptomatic individuals as compared with symptomatic individuals, we applied the test accuracy for symptomatic patients, however, we assumed that the lower boundary of the 95% confidence interval more accurately reflected test performance in the asymptomatic population. We display the summary of findings table for an intermediate prevalence setting (0.5% to 2%) in Table 2 . The benefits and downsides (or pros and cons of a pre-testing strategy are summarized in Figure 3 . The major benefits include: reassurance to endoscopy staff and other patients, potential reduction in transmission by deferring procedures in patients who test positive for SARS-CoV2, and informed decisions regarding use of PPE. Risk of transmission amongst healthcare workers, including in an endoscopy setting, has been reported to range from 4.3% to 21%. [32] [33] [34] Addressing safety concerns is an important aspect to resuming endoscopy operations for both endoscopists and patients. 35, 36 The downsides include perceived patient burden and limited availability of testing, logistics and bottleneck of testing for providers, and false positive and false negative results. For patients, false positive cases may lead to unnecessary case delay, self-quarantine and consequences for patient/family and ability to work and false negative cases may lead false reassurance and potential for increased transmission. For providers, false negative cases may lead to a potential increased risk for infection. The panel made a conditional recommendation for pre-procedural testing in areas where the asymptomatic prevalence of infection ranges between 0.5% and 2%. A conditional recommendation implies that most clinicians would follow the recommended course of action but many would not and that different approaches would be reasonable. The panel considered the number of false positives and false negatives, the downstream consequences of these test results, the net benefits and downsides of testing, and resource considerations. In developing this recommendation, the panel evaluated the hypothetical impact of a pre-testing strategy in an intermediate prevalence setting where the prevalence of SARS-CoV2 infection is between 0.5% and 2%. Based on our meta-analysis of studies that were at low risk of bias, the commercially available tests in the US have an estimated pooled sensitivity of 93% and specificity of 97% in symptomatic individuals. The panel assumed a sensitivity of 85% and specificity of 94% (these estimates were derived from our pooled meta-analysis of currently available commercial tests and represent the lower boundary of the 95% CI (which more likely reflects test accuracy in asymptomatic individuals). At a prevalence of 0.5%, in a sample of 1000 asymptomatic individuals who undergo the test, 64 will have a positive test result; of the 64 individuals with a positive result, 4 will be true positives but 60 will be false positives. At a prevalence of 2%, in 1000 asymptomatic individuals, -Limited ability to test patients will become a bottleneck in resuming endoscopy operations -If CDC or hospital guidance require it, additional tests showing 2 negative PCRs will be needed to clear patients prior to resuming work and rescheduling the procedure, in an already limited testing setting 76 individuals will have a positive test result and 17 will be true positives but 59 will be false positives. With respect to the number of false negatives, in a sample of 1000 asymptomatic individuals, at a prevalence of 0.5%, 1 individual out of 1000 will have a false negative result and at a prevalence of 2%, 3 individuals out of 1000 will have a false negative result (Figure 4) . As the prevalence increases, the proportion of false positives decreases. In our hypothetical example, the percentage of asymptomatic individuals who would test positive ranges from 6% to 22%. Individual endoscopy practices may use an interactive tool and input the local prevalence of infection in asymptomatic individuals (see implementation consideration section), input the sensitivity and specificity of the test used in their local setting, and determine the number of false positive and false negative results. In settings where testing is feasible and there is less perceived burden on patients, when the benefits outweigh the downsides, an endoscopy center may reasonably choose to implement a pre-testing strategy. Among individuals that test negative, endoscopists should use surgical masks for all upper and lower endoscopies. Endoscopists who are willing to accept the potential (albeit small) risk of infection from false positives (in an intermediate prevalence with a hypothetical sample of 1000 individuals, the number of false negatives would range from 1/1000 to 3/1000). Endoscopists who are unwilling to accept the small risk of infection may use N95/N99 respirator or PAPRs for upper and/or lower endoscopies. Alternatively, an endoscopy center may reasonably choose not to implement a pre-testing strategy and proceed with using higher PPE (N95/N99 respirators or PAPRs) for all procedures. In settings where the prevalence of asymptomatic infection is low (<0.5%), the downsides of a pre-testing strategy may outweigh the benefits. The downsides include the burden of testing prior to endoscopy and that the high number of false positives (~90% of the asymptomatic individuals who test positive for SARS-CoV2 will be false positives). Consequently, these individuals will have to cancel their procedure and be required to self-quarantine for 14 days. The survey conducted by our team (Table 2) found a wide distribution of risk aversion thresholds in the GI community. A minority of gastroenterologists (25.7%) had a low risk aversion threshold and were willing to accept a 1 in 1,000 risk of transmission. For this subset of gastroenterologists, surgical masks may be an acceptable option. For the remaining and therefore majority of gastroenterologists, N95s/N99 respirators or PAPRs should be utilized for all upper and/or lower endoscopies. Recommendation 3: For a small number of endoscopy centers in high prevalence areas, the AGA suggests against implementing a pre-testing strategy. In "hotspots", endoscopy may be reserved for emergency or time-sensitive procedures with use of N95/N99 respirators or PAPRs for all procedures. In settings where the prevalence of asymptomatic infection is high (>2%), the downsides of a pre-testing strategy may outweigh the benefits. The downsides include the unacceptable rate of false negatives (asymptomatic individuals who test negative for SARS-CoV2 who actually have infection). Consequently, these individuals will be given false reassurance. Based on our survey results for thresholds for risk aversion, endoscopists were unwilling to accept the small risk of increased infection due to false negatives and thus may opt to use higher PPE. Furthermore, in high-risk settings, testing may be limited and allocated to symptomatic individuals as opposed to asymptomatic individuals. However, if testing is available, a pre-testing strategy may be implemented for triaging asymptomatic individuals undergoing outpatient elective procedures. Recommendation 4: For all endoscopy centers, the AGA recommends against serologic testing as part of a pre-testing strategy for patients or endoscopy staff. -The evidence supporting the role of seroconversion for return to work or hospital staffing policies is also lacking. A recently published systematic review from the Cochrane Collaboration showed that serologic tests to identify different immunoglobulins (IgM, IgG, and/or IgA) against SARS-CoV-2 may identify individuals who had prior or recent infections. 37 However, the conclusion was informed by studies of symptomatic hospitalized patients and it is not clear how the tests will perform in asymptomatic individuals, which is the case when we are assessing individuals prior to endoscopy. Additionally, the presence of specific immunoglobulins does not necessarily indicate acute versus recent infections; IgM antibodies were identified in about 55% of patients after 35 days of disease onset, while IgG antibodies were identified in 30% of patients within the first week after disease onset. Finally, it is still not clear whether prior SARS-CoV-2 infection or harboring antibodies against SARS-CoV-2 will lead to protection against future infections. The limitations of this guideline are outlined below. The data about the prevalence of asymptomatic individuals was limited, and our prevalence estimates were informed by small clinical studies and indirect evidence from statistical models. [29] [30] [31] Similarly, our search strategy did not identify studies that assessed the diagnostic accuracy of the available tests in asymptomatic individuals. Thus, we used indirect evidence from symptomatic individuals and assumed that the tests will like underperform in those individuals. Additionally, the field is rapidly evolving and further studies on the diagnostic accuracy of the available tests may have been published after our search strategy deadline. Furthermore, the currently available tests were all authorized by the FDA under EUA and may become unavailable in the future. With respect to our estimates of diagnostic test accuracy, the included studies were all case-control studies, which are associated with overestimation of diagnostic performance measures. Finally, our recommendations do not take into account cost or economic impact of pre-testing strategies as we did not perform formal economic analyses. However, we would also highlight the strengths of our guidelines. We used rigorous methodology to systematically pool diagnostic accuracy results for commercially-available tests in the U.S. We also relied on gastroenterologists' reporting of risk aversion to help inform recommendations about the use of PPE based on survey results. While the survey included only 75 responses, the survey was valuable in informing the panel's understanding of the variability in thresholds for risk aversion. In the absence of such data, judgments about risk acceptance would have been based on inferences made by panel members of their own individual risk thresholds. Our recommendations account for geographic variability in prevalence of SARS-CoV2 infection (specifically focusing on the asymptomatic population) which directly impact test performance and allow for more informed decision-making. Finally, we developed an interactive online tool for gastroenterologists to assist groups in making an individualized decision for their local setting based on their local prevalence and locally available test and provide a framework for how test results can inform decisions regarding triage and PPE use. Our guidelines align with recommendations from other GI societies with the following distinctions: first, we emphasize the importance of determining the prevalence asymptomatic SARS-CoV2 infection and second, we highlight the uncertainty around test performance in asymptomatic individuals as clinical validation studies of currently available tests were conducted only in symptomatic patients with known or suspected COVID-19). [38] [39] [40] Furthermore, an economic analysis showed that RT-PCR testing is an effective strategy to re-start endoscopic practice, and similar to our guideline, highlighted the importance of accounting for local availability of testing, disease prevalence and the downstream consequences of false positive and negative results. 5 Universal preparations for endoscopy Regardless of whether a pre-testing strategy is adopted, several measures are essential to establishing a safe working environment for endoscopy. This checklist was created using recommendations from the CDC, with modifications relevant for an endoscopy center (Table 3 ). 41 Table 3 : Checklist for Endoscopy Re-Opening 1. Pre-arrival symptom screening for patients using the CDC checklist. 42 2. Limit entry of individuals of non-essential individuals (patients, visitors, staff) 3. All individuals (patients, visitors, staff) should wear masks at all times, unless access to the nose or mouth are necessary for patient care. When space is limited, consider providing alternate areas for visitor waiting and/or requesting for visitors to wait outside of the facility 6. Per institutional and local governmental protocols, additional consent regarding the risks of contracting COVID-19 may be required 7. Frequent and scrupulous hand hygiene for all individuals in the healthcare facility. 8. Ensure best practices in donning, doffing and disposal of PPE 9. Appropriate disposal of all single use equipment after use and decontamination of reusable equipment strictly in line with the manufacturer's instructions One important consideration is that the CDC screening checklist includes several GI symptoms, such as diarrhea. Prior AGA meta-analysis and guideline found that isolated GI symptoms (in the absence of other COVID-19 URI symptoms) are rare. 43 Furthermore, when they do occur as an atypical manifestation of COVID-19, other symptoms typically follow within 1-5 days. If a patient presenting for endoscopy has nausea, vomiting, or diarrhea for >5 days without the development of other COVID-19 symptoms, it is reasonable to consider them as "negative" per the CDC screening checklist. Use of an online interactive tool to determine whether or not to adopt a pre-testing strategy for endoscopy In order to determine whether a testing strategy should be utilized, our team has created a new online tool available on AGA's website to tailor decision-making to your local setting (https://gastro.org/practice-guidance/practice-updates/covid-19). This resource utilizes inputted prevalence data, along with diagnostic test accuracy data, to determine the downstream consequences of testing, such as false positive and false negative rates. First, determine local prevalence in your area. There are several approaches that can be used. We present them here in order of preference after acknowledging the limitation of each method: 1. The use of locally available data from health systems that have been conducting screening for asymptomatic individuals in outpatient settings using nucleic acid amplification tests. This is likely the most accurate estimation of the prevalence of asymptomatic individuals. For example, if your endoscopy center has already employed a pre-testing strategy, obtaining this data to calculate prevalence would be most directly applicable. 2. The use of locally available data from local public health departments regarding the prevalence of the asymptomatic individuals or, if not available, the disease overall. This approach may overestimate or underestimate the prevalence of asymptomatic individuals depending on the availability and indications for testing in the area. 3. The use of publicly available data about the state or county through the Centers for Disease Control (CDC) website, The COVID Tracking Project, and the COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University. The websites provide the proportion of positive tests in the area. Unpublished data and the available models suggest that for each diagnosed symptomatic patient there may be 10 asymptomatic or undiagnosed individuals in the area. 29, 30 This can be used to estimate the prevalence in the area by using the number of diagnosed cases over the past 2 weeks and the publicly available data about population count in each area. The use of the proportion of positive tests alone is likely an overestimation of the prevalence and should not be used alone to assess the prevalence. The following steps for calculating state prevalence in the asymptomatic population for input in iSOF. For more granular data that may be more relevant to your local setting, see Supplement The diagnostic test characteristics are defaulted to the pooled sensitivity and specificity derived from our meta-analysis described above, which encompasses commercially-available US tests. This can, however be customized to reflect performance of locally available tests in an individual setting. Of note, the lower end of the confidence interval is utilized given that these data are taken from symptomatic populations, and testing accuracy is likely to be lower for asymptomatic patients. If your local test is an institutional laboratory-derived test, the sensitivity and specificity may differ. This can be modified in the online tool as well. Third, based on assumptions of prevalence and test accuracy, the online tool will provide information on the false negative rate and false positive rate in your local setting (Figure 4 ). In intermediate prevalence areas, tradeoffs of testing should be considered ( Figure 3) to help decide if a pre-testing strategy is implemented. The matrix shown in Figure 5 takes into account testing availability and PPE availability. This highlights that if testing capacity is severely limited, a no-testing approach is reasonable, regardless of prevalence. In this scenario, PPE use is determined by availability and risk aversion threshold of endoscopists. In a high prevalence area, the highest level of PPE should be worn. In a low prevalence area, risk aversion thresholds will be the determining factor for PPE decision-making. Do not pursue testing strategy (high false +s) -Consider wearing surgical masks for lower endoscopy, and N95s for upper endoscopy depending on PPE availability and risk aversion threshold High prevalence area ("hotspot"): Do not pursue testing strategy (high false -s) --Wear highest level of PPE (N95s/PAPRs) and reserve endoscopy for time-sensitive procedures Low prevalence area: Do not pursue testing strategy (high false +s) -Consider wearing surgical masks for lower endoscopy, and N95s for upper endoscopy depending on PPE availability and risk aversion threshold High prevalence area ("hotspot"): Do not pursue testing strategy (high false -s) -Wear highest level of PPE (N95s/PAPRs) and reserve endoscopy for time-sensitive procedures procedure testing and specimen collection. If not, setting up testing at your endoscopy center can be considered. It is important to maximize test performance using high quality specimen collection and sampling technique, as outlined in the Supplement Table 5 . Test result follow-up should occur in a timely fashion. In the event of a positive result, patients should be notified according to local institutional policies, with instructions to self-isolate accordingly. In some cases, repeat testing may be required to clear the patient for endoscopy, although this policy is controversial and not universal. Another consideration is that local prevalence may change over time and require reassessment of the implemented strategy, thus periodic re-evaluaton of prevalence to inform local endoscopy center practices will be necessary. The COVID-19 pandemic is a global economic, societal and health crisis. Procedural volumes have drastically declined to 60-80% of baseline volumes, indicating the impact on GI practices. 32, 44, 45 The provision of healthcare services including the re-introduction of endoscopy across healthcare systems and ambulatory care centers is critical to reducing the long-term consequences of this crisis. Ensuring safety for patients, staff and endoscopists is an important consideration in the resumption of endoscopy, however, endoscopy centers across the US face many unique challenges with respect to availability and access to testing, understanding geographic variability in SARS-CoV2 prevalence rates, and availability of PPE. In areas where testing is more widely available, the two main considerations that should drive the decision to implement a pre-testing strategy are local prevalence of SARS-CoV2 (in asymptomatic individuals) and diagnostic test performance (i.e. sensitivity and specificity). These test characteristics combined with prevalence drive the likelihood of obtaining false positive and false negative results. If a pre-testing strategy is implemented, it is important to consider the logistics of testing (for patients and endoscopy centers), the informative value of the test, and downstream consequences with respect to triaging of patients, ensuring safety with endoscopy, and PPE use. In areas where testing capacity is limited diverting limited resources for procedural testing of outpatient asymptomatic individuals prior to endoscopy may further compound the problem. Increasing the number of tests is essential but many areas struggle with rationing of tests and being able to provide test results in a timely manner. The online interactive tool created as a result of this guideline aims to help endoscopy centers determine the downstream effects of implementing a pretesting strategy. (add link to AGA guideline page). We provide guidance for gastroenterologists to calculate the prevalence of SARS-CoV2 infection in asymptomatic individuals, input sensitivity and specificity of their local test, and determine the rates of positive and negative tests to help guide decision making. Periodic re-evaluaton of prevalence to inform local endoscopy center practices is recommended in light of geographic variability and predictions of more surges over the next 12-18 months. Manuscript: Table 1: Executive Summary of Recommendations Table 2 : Survey respondent characteristics by risk aversion threshold Table 3 : Checklist for Endoscopy Re-Opening Table 4 . How to calculate the prevalence of asymptomatic SARS-CoV2: case example Figure 1 : Forest plot of test accuracy (pooled sensitivity and specificity) all studies Figure 2 : GRADE Summary of Findings Table of Test Accuracy Results for Prevalence of 0.5%, 1%, 2% of SARS-Co2 Infection in Asymptomatic Individuals Figure 3 : Considerations for adopting a pretesting strategy in intermediate prevalence settings Figure 4 : Online interactive tool for pre-procedure testing prior to endoscopy Figure 2 : Test accuracy (pooled sensitivity and specificity) of studies with low risk of bias Supplement Table 2 : Interpretation of the Certainty in Evidence of Effects using the GRADE framework We are very confident that the true effect lies close to that of the estimate of the effect. We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect Supplement The recommendation can be adapted as policy or performance measure in most situations Policy making will require substantial debate and involvement of various stakeholders. Performance measures should assess whether decision making is appropriate. * Strong recommendations are indicated by statements that lead with "we recommend", while conditional recommendations are indicated by statements that lead with "we suggest" Supplement Table 4 . QUADAS-2 Assessment of Risk of Bias for Diagnostic Test Accuracy Studies Source of specimen: Specimen sources for SARS-CoV-2 testing include nasopharyngeal (NP), mid-turbinate (MT), nasal, throat, or saliva. In symptomatic patients, a recent meta-analysis and guideline from the Infectious Disease Society of America (IDSA) suggests collecting NP or MT or nasal swabs rather than oropharyngeal swabs or saliva alone for diagnostic testing. 4 However, no recommendation was made for asymptomatic patients, which comprise our outpatient endoscopy population, as available data are limited. Collection technique also impacts diagnostic test accuracy. Particularly for nasopharyngeal sample collection, training is beneficial to ensure adequate specimen collection. A useful resource for NP sample technique is available from NEJM which includes both a description and video for training purposes. 50 Other technique instructions for diagnostic testing are available on the FDA's website. 51 Additionally, collection of specimens are most commonly performed by healthcare workers, but some tests allow for patient self-collection as well. Published guidance from the IDSA indicates that there is no role for self-collection of samples in asymptomatic individuals, and therefore this practice is not recommended in the context of endoscopy operations. 4 False negatives can result when there is inadequate specimen collection as described above, or the viral load is low and the test is unable to detect SARS-CoV2 at that threshold. Conversely, false positives can result because of cross-reactivity of other coronaviruses, or more commonly, specimen contamination. Aerosol generation occurs when air accelerates across a fluid surface and creates aerosols that contain virus. However, whether aerosol has infective potential is impacted by many factors, including where the fluid originates (e.g. upper airway, lower respiratory tract, upper or lower gastrointestinal tract) the amount of virus present in the aerosols, and how much aerosolization occurs (which may differ according to the procedure). Depending on the type of aerosol generating procedure and the risk of airborne transmission, PPE at the level of airborne protection may be indicated. In some locations, engineering modification can change a positive pressure room or entire ward to a negative pressure. Having a room with good ventilation, that is, a high rate of air exchanges, is likely to be more important than whether it is at positive or negative pressure. In hospitals, room ventilation will clear viral aerosols fairly quickly. Each 'air exchange' removes approximately 63% of the virus, after n room exchanges, the remaining viral load is 0.37 n . After two exchanges, there is 14% and after five air exchanges < 1% (0.37 5 ) of the original viral load in the room, respectively. If there are 12 air exchanges per hour, five exchanges will take 25 min. This may be the case in ICU. If there are 25 air exchanges per hour, five air exchanges will Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding A Novel Coronavirus Genome Identified in a Cluster of Pneumonia Cases -Wuhan A Novel Coronavirus from Patients with Pneumonia in China Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19 COVID-19 polymerase chain reaction testing before endoscopy: an economic analysis CDC's Diagnostic Test for COVID-19 Only and Supplies AGA Institute Rapid Recommendations for Gastrointestinal Procedures During the COVID-19 Pandemic The AGA institute process for developing clinical practice guidelines part one: grading the evidence QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews Meta-Analysis of Diagnostic Accuracy R: A Language and Environment for Statistical Computing: R Foundation for Statistical Computing GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy GRADE guidelines: 21 part 2. Test accuracy: inconsistency, imprecision, publication bias, and other domains for rating the certainty of evidence and presenting it in evidence profiles and summary of findings tables GRADEpro Guideline Development Tool Available from gradepro.org Plans to Reactivate Gastroenterology Practices Following the COVID-19 Pandemic: A Survey of North American Centers Comparison of Two High-Throughput Reverse Transcription-Polymerase Chain Reaction Systems for the Detection of Severe Acute Respiratory Syndrome Coronavirus 2 Multicenter Evaluation of the Cepheid Xpert Xpress SARS-CoV-2 Test Evaluation of the COVID19 ID NOW EUA assay Evaluation of the QIAstat-Dx Respiratory SARS-CoV-2 Panel, the first rapid multiplex PCR commercial assay for SARS-CoV-2 detection Performance of Abbott ID NOW COVID-19 rapid nucleic acid amplification test in nasopharyngeal swabs transported in viral media and dry nasal swabs, in a New York City academic institution Comparison of Commercially Available and Laboratory Developed Assays for in vitro Detection of SARS-CoV-2 in Clinical Laboratories Rapid and sensitive detection of SARS-CoV-2 RNA using the Simplexa COVID-19 direct assay Test Agreement Between Roche Cobas 6800 and Cepheid GeneXpert Xpress SARS-CoV-2 Assays at High Cycle Threshold Ranges Comparison of Cepheid Xpert Xpress and Abbott ID Now to Roche cobas for the Rapid Detection of SARS-CoV-2 Comparing the analytical performance of three SARS-CoV-2 molecular diagnostic assays Clinical Evaluation of Three Sample-To-Answer Platforms for the Detection of SARS-CoV-2 Analytical and Clinical Comparison of Three Nucleic Acid Amplification Tests for SARS-CoV-2 Detection Estimating COVID-19 Prevalence in the United States: A Sample Selection Model Approach Yield and Implications of Pre-Procedural COVID-19 PCR Testing on Routine Endoscopic Practice Implementation and Impact of Universal Preprocedure Testing of Patients for COVID-19 prior to Endoscopy Global Impact of the COVID-19 Pandemic on Endoscopy: An International Survey of 252 Centers from 55 Countries COVID-19 transmission among gastrointestinal endoscopists Low risk of covid-19 transmission in GI endoscopy Most Patients Are Willing to Undergo Elective Endoscopic Procedures During the Reopening Period of the COVID-19 Pandemic Endoscopy staff are concerned about acquiring COVID-19 infection when resuming elective endoscopy Antibody tests for identification of current and past infection with SARS-CoV-2 Proposal for the return to routine endoscopy during the COVID-19 pandemic American College of Gastroenterology Task Force on Endoscopic Resumption. The ACG Roadmap for Safely Resuming or Ramping-Up Endoscopy in the COVID-19 Guidance on Safely Reopening Your Endoscopy Center Guidance for Resuming GI Endoscopy and Practice Operation after the COVID-19 Pandemic Healthcare Facilities: Managing Operations During the COVID-19 Pandemic Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19) AGA Institute Rapid Review of the Gastrointestinal and Liver Manifestations of COVID-19, Meta-Analysis of International Data, and Recommendations for the Consultative Management of Patients with COVID-19 Protocols, Personal Protective Equipment Utilization and Psychological/Financial Stressors within Endoscopy Units in Mid-Pandemic: A Large Survey of Hospital-based and Ambulatory Endoscopy Centers in the Changes in Gastroenterology and Endoscopy Practices in Response to the COVID-19 Pandemic: Results from a North American Survey Emergency Use Authorization (EUA) to enable use of needed products in civilian and military emergencies, United States Diagnostic Testing for the Novel Coronavirus Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised) COVID-19) Emergency Use Authorizations for Medical Devices How to Obtain a Nasopharyngeal Swab Specimen Food and Drug Administration. FAQs on Testing for SARS-CoV-2. Medical Device Safety: Emergency Situations Until the room is clear of aerosol (the viral clearance period), the level of PPE worn should be at the level of airborne protection The authors thank Erica Wilson and Jacob Matheny for their invaluable support and assistance. Conflict of Interest Disclosure: All members were required to complete the disclosure statement. These statements are maintained at the American Gastroenterological Association (AGA) headquarters in Bethesda, Maryland. The authors declared no competing financial interests. No internal or external funding was used to support the development of this guideline. What kinds of SARS-CoV2 diagnostic tests are currently available in the U.S.? On February 4th, 2020, the HHS Secretary determined there is a public health emergency which justified the authorization of emergency use of in vitro diagnostics for COVID-19. Commercial manufacturers and clinical laboratories were required to submit details about SARS-CoV-2 assays to the U.S. FDA for review and emergency use authorization (EUA).EUA was established as part of the Project BioShield Act of 2004 and allows the FDA to issue emergency approval of drugs, devices, and diagnostic tests to help combat a crisis. 46 The regulations to obtain approval differs substantially from the standard FDA approval process. While the FDA does not typically regulate laboratory tests, in the setting of an EUA, the FDA is issued the authority to establish which laboratory tests can be used and what testing standards are needed prior to obtaining FDA approval. 47 In the setting of a public health emergency, the FDA only requires a standard of "may be effective" to approve a diagnostic test. To achieve this, test developers are expected to test their assay against a minimum 30 positive samples and 30 negative samples. 48 Ideally positive clinical samples are recommended but contrived reactive specimens can be used as well. While these standards are significantly lower than what is typically needed to obtain approval for a new diagnostic test, the EUA allows the FDA to review this limited data and issue approval. Importantly, once the public health emergency is discontinued, EUAs are no longer in effect and manufacturers must submit standard data requirements supporting their test's diagnostic accuracy. Multiple commercial test manufacturers and clinical laboratories, including academic medical centers, have received EUA for a SARS-CoV2-specific molecular diagnostic test. As of July 8, 2020, 16 th , 104 tests have received EUA. 49