key: cord-0989923-gxrme9bv
authors: Barnacle, James R.; Houston, Hamish; Baltas, Ioannis; Takata, Junko; Kavallieros, Konstantinos; Vaughan, Natalie; Amin, Amit K.; Aali, Sayyed Adnan; Moore, Kisha; Milner, Piers; Wright, Ankur Gupta; John, Laurence
title: Diagnostic accuracy of the Abbott ID NOW SARS-CoV-2 rapid test for the triage of acute medical admissions
date: 2022-02-23
journal: J Hosp Infect
DOI: 10.1016/j.jhin.2022.02.010
sha: 66c06696ae171055fa743a626ebf75dae18456a2
doc_id: 989923
cord_uid: gxrme9bv

BACKGROUND: Decisions to isolate patients at risk of having COVID-19 in the emergency department must be rapid and accurate to ensure prompt treatment and maintain patient flow whilst minimising nosocomial spread. Reverse transcription polymerase chain reaction (RT-PCR) assays are too slow to achieve this, and near-patient testing is being used increasingly to facilitate triage. The ID NOW SARS-CoV-2 assay is an isothermal nucleic acid amplification near-patient test which targets the RNA-dependent-RNA-polymerase gene. AIM: To assess the diagnostic performance of ID NOW as a COVID-19 triage tool for medical admissions from the emergency department of a large acute hospital. METHODS: All adult acute medical admissions from the ED between 31(st) March to 31(st) July 2021 with valid ID NOW and RT-PCR results were included. The diagnostic accuracy of ID NOW (sensitivity, specificity, positive predictive value, negative predictive value) was calculated against the laboratory reference standard. Discrepant results were further explored using cycle threshold values (Ct) and clinical data. FINDINGS: 2.0% (124/6050) of medical admissions were SARS-CoV-2 positive on RT-PCR. Compared to PCR, ID NOW had a sensitivity and specificity of 83.1% (95% CI:75.4–88.7) and 99.5% (95% CI:99.3–99.6) respectively. Positive (PPV) and negative predictive values (NPV) were 76.9% (95% CI:69.0–83.2) and 99.6% (95% CI:99.5–99.8). The median time from arrival in the ED to ID NOW result was 59 minutes. CONCLUSION: ID NOW provides a rapid and reliable adjunct for the safe triage of COVID-19 and can work effectively when integrated into an ED triage algorithm.

Background Decisions to isolate patients at risk of having COVID-19 in the emergency department must be rapid and accurate to ensure prompt treatment and maintain patient flow whilst minimising nosocomial spread. Reverse transcription polymerase chain reaction (RT-PCR) assays are too slow to achieve this, and near-patient testing is being used increasingly to facilitate triage. The ID NOW SARS-CoV-2 assay is an isothermal nucleic acid amplification near-patient test which targets the RNA-dependent-RNA-polymerase gene.

To assess the diagnostic performance of ID NOW as a COVID-19 triage tool for medical admissions from the emergency department of a large acute hospital.

All adult acute medical admissions from the ED between 31 st March to 31 st July 2021 with valid ID NOW and RT-PCR results were included. The diagnostic accuracy of ID NOW (sensitivity, specificity, positive predictive value, negative predictive value) was calculated against the laboratory reference standard. Discrepant results were further explored using cycle threshold values (Ct) and clinical data. 19 , an acute respiratory viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to place a huge burden on secondary healthcare facilities. By the end of 2021, 640,829 patients had been admitted to hospital with COVID-19, with a 7-day rolling average of 2183 daily admissions across the United Kingdom (UK) [1] .

The symptoms of COVID-19 may be non-specific, and a diagnosis cannot be made or refuted based on clinical criteria and radiology alone [2, 3] . Fast and effective triage is vital to the safe functioning of a hospital, and decisions to isolate patients at risk of COVID-19 must be rapid and accurate to ensure prompt treatment and maintain patient flow whilst minimising nosocomial spread [4] . Patients admitted from the Emergency Department (ED) with suspected or possible COVID-19 and an outstanding SARS-CoV-2 test must be isolated from other patients pending the result.

The gold standard for diagnosis is reverse transcription polymerase chain reaction (RT-PCR) from a nasopharyngeal swab (NPS), but even the fastest available assays have a run time of 45 minutes or more and require laboratory-based technological expertise and equipment [5, 6] . Sample transport, ribonucleic acid extraction, and result reporting add further to PCR turnaround time. Laboratorybased PCR results are therefore too slow to make isolation and treatment decisions in the ED [7] .

Several rapid tests have emerged to allow the prompt diagnosis and triage of COVID-19 patients [4, 8] . Accurate near-patient testing plays a crucial role in triage and admission pathways, allowing prompt initiation of specific COVID-19 treatment and optimal use of bed capacity, as well as ensuring other conditions can be managed effectively without the risk of nosocomial spread.

The ID NOW COVID-19 assay (Abbott Diagnostics, Il, USA) is an isothermal nucleic acid amplification test which targets the unique region of the RNA-dependent RNA polymerase (RdRp) gene. The instrument uses dry nasal swabs, has a small footprint, is user-friendly and does not require additional equipment, making it ideal for use as a 'near-patient' test for EDs. The run time is as little as five minutes for a positive result, and 13 minutes for a negative result [9] . Results can be integrated automatically with hospital records which saves time and error by avoiding manual recording, and allows easy evaluation and audit. The reported performance of ID NOW in the literature to date has mostly come from small studies across a range of settings, with sensitivities ranging from 55-98% and specificities 95-100% when using RT-PCR as the gold standard [8, [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] . Sensitivity approaches 100% when PCR results with a cycle threshold (Ct) value >30, suggesting a lower viral load, are excluded [15, [19] [20] [21] . Here we describe the real-world diagnostic performance of ID NOW as a COVID-19 triage tool in the ED of a large acute hospital. This, to our knowledge, is the largest single real-world study of the diagnostic performance of ID NOW, and the first to study its routine use in consecutive medical admissions in the United Kingdom (UK).

We used data prospectively entered into a near-patient testing database and retrospectively extracted from electronic patient records at Northwick Park Hospital, a large 600-bed district general hospital serving a diverse population in North-West London. Prior to the pandemic, the hospital received over 100,000 ED attendances and 50,000 medical admissions each year. Patients were included in the study if they were aged 16 years or more on arrival to ED and required admission to a medical ward between 31 st March to 31 st July inclusive.

J o u r n a l P r e -p r o o f

During the study period, all patients who presented to ED were triaged at initial assessment by the attending clinician according to their risk of COVID-19 as 'likely', 'uncertain' or 'unlikely' (Table A.1) . In brief, patients with a clinical syndrome or chest radiology consistent with COVID-19, a COVID-19 contact history or a positive PCR or lateral-flow antigen test (LFT) result within 14 days prior to arrival were classified as 'likely'. Those with fever, cough, shortness of breath, diarrhoea, abdominal pain and/or confusion not meeting the 'likely' criteria were classified as 'uncertain', with others being classified as 'unlikely'. Isolation in a side room or admission to a COVID-19 cohort area was based on clinical risk of COVID-19 and ID NOW result.

All patients were tested for SARS-CoV-2 with ID NOW, except those who had a positive community SARS-CoV-2 PCR between 14-90 days before arrival and were asymptomatic. A positive ID NOW result in such patients would likely represent a post-infectious period rather than a current infection with risk of onward transmission. A dry nasal swab was taken by an ED nurse and tested in the ED by trained technicians using the ID NOW platform as per the manufacturer's instructions-for-use (IFU) [9] . If the first ID NOW result was invalid, the test was repeated a second time. Those requiring medical admission had a separate nasopharyngeal swab (NPS) sent to the laboratory in viral transport media (VTM) for SARS-CoV-2 PCR testing. Laboratory SARS-CoV-2 testing was done using either the Panther Fusion SARS-CoV-2 (Hologic Inc, CA, USA), Abbott RealTime SARS-CoV-2 (Abbott Park, IL, USA), an extraction-free SARS-CoV RT-PCR assay developed by Health Services Laboratories (UK) [22] , Xpert Xpress SARS-CoV-2 (Cepheid, CA, USA) or SAMBA II SARS-CoV-2 (Diagnostics for the Real World, CA, USA).

Consecutive adult medical admissions from the ED with valid ID NOW results were included. Patients without a valid ID NOW result on admission or a valid PCR result within 48 hours of admission were excluded from the analysis. ID NOW results and the time the result became available were recorded prospectively. Time of arrival, demographic data, vital signs including National Early Warning Score (NEWS) on arrival to ED, laboratory PCR results, and thoracic imaging reports were extracted retrospectively from electronic patient records and hospital IT systems.

The diagnostic performance of ID NOW for detecting COVID-19 was estimated using a single RT-PCR reference standard. Patients were defined as having COVID-19 or not based on the first valid PCR result up to 48 hours after admission. Given that a single PCR is not a perfect reference standard [3] , discrepant results were further explored using the RT-PCR cycle threshold (Ct) value, admission symptoms, chest x-ray report, discharge diagnosis, community SARS-CoV-2 results prior to admission (PCR and LFT) and further PCR results later in admission. Where Ct values for more than one gene target were available for a single PCR result, the lowest value was taken.

The time between arrival to ED and a valid ID NOW result becoming available was calculated. Thoracic imaging was reported and coded based upon guidelines on COVID-19 from the British Society of Thoracic Imaging (BSTI) at the time of reporting by radiologists [23] .

Using laboratory-based RT-PCR as the reference standard, we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for ID NOW. Baseline characteristics were compared using Wilcoxon rank-sum for continuous variables and Pearson's chisquared for categorical variables. Kaplan-Meier time-to-event analysis was used to describe ID NOW result data and the log rank test used to compare groups. All statistical tests were two-sided at α value of 0.05. All statistical analyses were performed using Stata version 17.0 (StataCorp, LLC, TX, USA).

Ethics ID NOW testing was part of routine care to support the diagnosis and triage of COVID-19 patients. The study was approved by the London North West University Hospitals NHS Trust Research and Development Committee. Since the study used routinely collected clinical data, formal ethical approval and patient consent was not required. Results are reported in compliance with STARD guidelines [24] .

Between 31 st March and 31 st July 2021, valid ID NOW and RT-PCR results were available at admission for 6050/6473 (93.5%) patients ( Figure 1 ). Of the admissions without valid paired results, 102 had had a recent COVID-19 infection, 15 had tested negative by ID NOW during a separate attendance within 24 hours prior to arrival, 60 were admitted directly to the hyper-acute stroke unit, five refused ID NOW testing and 87 had no ID NOW result for unknown reasons. None had an invalid ID NOW result that was not resolved by running the assay a second time. Median age was 71 years, there were similar numbers of men and women, and median NEWS score was 2 (Table I) .

Overall, the median time between arrival in ED and ID NOW result was 59 minutes (IQR 37 -107) ( Figure 2A ). The median time to result for admissions requiring oxygen on arrival was shorter (39 minutes) ( Figure 2B) . Both patients were young males who presented with non-COVID-19 related issues and may represent poor sampling with the dry nasal swab.

Here we present a large real-world evaluation of the Abbott ID NOW rapid test within a front-door COVID-19 triage algorithm for adult medical admissions. We demonstrate a sensitivity and specificity of 83.1% and 99.5% respectively compared with RT-PCR. This meets the acceptable performance characteristics for sensitivity (>80%, CI: 70-100%) and desirable characteristics for specificity (>99%, CI: 97-100%) according to the UK government target product profile for SARS-CoV-2 rapid testing [25] . These estimates of diagnostic accuracy were derived from real-world data from a busy ED in a large district general hospital as part of routine care. The median time from arrival in ED to ID NOW result was less than one hour. Results were therefore available fast enough to inform bed allocation before patients needed to be moved to a ward, likely improving infection control and reducing nosocomial spread of SARS-CoV-2. Clinicians prioritised rapid testing for the most unwell patients, particularly those requiring supplemental oxygen on arrival. Rapid and specific diagnosis of COVID-19 may reduce delays to life-saving treatments in such patients.

Our results are in keeping with previously published data which have shown sensitivity with respect to RT-PCR of 70.3-98.0%, and specificity of 95.3-100% [8, 10, 13, 17, 18, 20, 21, 26] . A Cochrane review published in March 2021 included 12 studies with an overall prevalence of 634/1853 (34.2%), and reported sensitivity 78.6% (95% CI: 73.7-82.8%) and specificity 99.8% (95% CI: 98.7-99.9%), although most studies did not use dry nasal swabs as per manufacturer IFU. When limited to those studies adherent to IFU, sensitivity fell to 73.0% (95% CI: 66.8-78.5) and specificity 99.7% (95% CI: 98.7-99.9%), with a prevalence of 222/812 (27.3%) [27] . This may be because studies following IFU were more likely to be real-world studies which are less controlled, with limitations such as sample quality. LFDs are an alternative approach to isothermal NAAT for SARS-CoV-2 rapid testing in the ED [28] . In a large meta-analysis not confined to use in the ED, LFDs had a pooled sensitivity of 76.3% (95% CI: 73.1% to 79.2% when manufacturer's IFU were followed [29] . Along with improved sensitivity, ID NOW has a faster turnaround time than LFDs, and results can be automatically integrated into electronic records.

There have been few trials in lower prevalence clinical settings. We found ID NOW performed well at 2.0% prevalence. Tu et al evaluated 974 patients in an outpatient clinic setting and found a prevalence of 2.4%, positive percentage agreement (PPA) 91.3% and negative percentage agreement (NPA) 100%, with only two false negatives, with Ct values of 36.5 and 38.1 [17] . Another large cohort taken from asymptomatic pre-operative outpatient screening found four cases in 1100 screened (prevalence 0.36%) with an excellent NPA of 99.7% [30] .

Of the 5926 negative PCR results, 31 patients tested positive on the ID NOW. Such 'false positives' may arise because of detection of residual viral RNA following recent infection in individuals who are post-infectious (likely explanation in 5/31), or because a single SARS-CoV-2 PCR is an imperfect reference standard and may itself miss individuals with current infection (likely in 9/31) [3] . Stokes et al found that on further evaluating nine ID NOW false positives, 5/9 were PCR positive on repeat testing of the same sample using different assays [15] . Our remaining false positives may represent asymptomatic COVID-19 with a false-negative PCR [31, 32] or contamination. In our study, technicians performing the ID NOW assay conducted regular work-surface decontamination and environmental swabs as quality control, likely limiting false positives. Such measures must be implemented to ensure applicability of our results to other settings, especially in the context of busy EDs.

Sensitivity of ID NOW was related to the Ct value reported by the reference RT-PCR assay. PCRpositive admissions with lower Ct values, suggesting higher viral load and greater infectiousness, were more likely to be detected by ID NOW (sensitivity for cases with Ct <30: 95.6%, Ct ≥30: 60.0%). This real-world observation is corroborated by the UK Technologies Validation Group report, and other data [17, [19] [20] [21] [33] [34] [35] , and explained by the fact that isothermal amplification has a higher limit of viral detection than RT-PCR [36] . We observed two false-negative cases with low Ct values which may have occurred due to inadequate sampling.

The strengths of this study are its pragmatic design under routine clinical settings, large sample size and that we are able to account for 93.5% of medical admissions, reducing risk of bias. There are, however, some limitations. A single SARS-CoV-2 RT-PCR is an imperfect reference standard and does not account for PCR-negative patients with COVID-19. Specificity of ID NOW may therefore be underestimated. We mitigated this through detailed investigation of discrepant results. Several PCR platforms were used and Ct values across different assays are inconsistent [37] , limiting generalisability of our estimates of ID NOW sensitivity by Ct value. This is the nature of a real-life study; a combination of platforms is required to serve the needs of the hospital.

Moreover, 39.5% of the PCR-positive results did not have a Ct value which limits the interpretation of false negatives. This was unavoidable as some laboratory assays did not produce a Ct value. There are also technical limitations to ID NOW itself. Unlike most RT-PCR assays, it has a single gene target, which leaves it vulnerable to false negatives if there is target failure in a future variant. This could be corrected relatively easily once identified by altering its primers. The ID NOW assay also lacks a human control target such as RNase P, so cannot identify inadequate sampling.

Near-patient rapid SARS-CoV-2 testing is an essential tool to ensure prompt COVID-19 treatment, maintain patient flow, and minimise nosocomial transmission in acute hospitals. ID NOW provides a rapid and reliable adjunct to the safe triage of COVID-19 and can work effectively when integrated into an emergency department triage algorithm. Reduced sensitivity compared with RT-PCR can be mitigated by applying clinical criteria within such an algorithm to ensure that negative results in patients with high pre-test probabilities are interpreted cautiously.

The authors declare no conflicts of interest.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 

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We would like to acknowledge all the clinical staff at Northwick Park Hospital who care for the patients involved in this study, in particular the near-patient testing team.