key: cord-0876597-40e11why authors: Lippi, Giuseppe; Nocini, Riccardo; Mattiuzzi, Camilla; Henry, Brandon M. title: FebriDx for rapid screening of patients with suspected COVID-19 upon hospital admission: systematic literature review and meta-analysis date: 2022-02-21 journal: J Hosp Infect DOI: 10.1016/j.jhin.2022.02.009 sha: 287b3ff74e9e6b9bbbae81a184668f199be8e55a doc_id: 876597 cord_uid: 40e11why In this study we performed a systematic literature review and meta-analysis of the lateral flow-based FebriDx immunoassay for triaging patients with suspected coronavirus disease 2019 (COVID-19) upon healthcare facilities admission. We conducted an electronic search in Scopus and Medline with the keywords “FebriDx” AND “COVID-19” OR “SARS-CoV-2”, with no language or date (i.e., up to February 4, 2022) limits, selecting studies where FebriDx was used for triaging patients for suspected COVID-19 in acute care settings, reporting sufficient data for constructing a 2×2 table. Five studies were finally included in our analysis, totalling 2309 patients. The pooled diagnostic sensitivity and specificity were 0.91 (95%CI, 0.88-0.93) and 0.92 (95%CI, 0.90-0.93), whilst the area under the curve (AUC), accuracy and kappa statistics were 0.971 (95%CI, 0.962-0.980), 91.4% (95%CI, 90.2-92.5%) and 0.762 (95%CI, 0.731-0.793), respectively, thus reflecting a substantial agreement with reference molecular testing techniques. The negative (NPV) and positive (PPV) predictive values were 0.974 (95%CI, 0.966-0.981) and 0.742 (95%CI, 0.711-0.770), respectively. In conclusion, our pooled analysis demonstrates that FebriDx has clinical value for rapid screening of patients with suspected COVID-19 in acute care settings, especially in regions with high viral circulation in which the pre-test probability is high and enables prioritization for confirmatory laboratory testing. In this study we performed a systematic literature review and meta-analysis of the lateral flow-based FebriDx immunoassay for triaging patients with suspected coronavirus disease 2019 (COVID-19) upon healthcare facilities admission. We conducted an electronic search in Scopus and Medline with the keywords "FebriDx" AND "COVID-19" OR "SARS-CoV-2", with no language or date (i.e., up to February The use of rapid and accurate coronavirus disease 2019 (COVID-19) screening tools is essential in healthcare settings, especially upon hospital or emergency department (ED) admission, where rapid diagnosis or rule out of severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) infection can enable more appropriate and timely treatment of symptomatic patients, as well as the dedicated triage of subjects with asymptomatic infection seeking care for other pathologies, who may be responsible for nosocomial transmission, potentially leading to large hospital clusters [1, 2] . Although the use of traditional, laboratory-based nucleic acid amplification assays (NAATs) remains the gold standard for detecting viral RNA and hence accurately diagnosing SARS-CoV-2 infection, the systematic use of these techniques for screening patients is inherently unfeasible, mostly due to low throughput and relatively long turnaround time [3] . Neither the surrogate nor subsidiary usage of rapid molecular assays as point-of-care (POC) at the site of patient admission seems a pervasive solution, since the accuracy of certain of these methods is considerably lower compared to laboratory-based NAATs (as low as 0.60), and these devices are not constitutively suited to manage large volumes of tests [4] . This last aspect has garnered magnified relevance with the dramatic surge of COVID-19 cases occurred worldwide after the emergence of the highly contagious SARS-CoV-2 Omicron variant [5] . Several approaches have been proposed for rapid screening of patients for COVID-19 during the pandemic in acute care settings, including the use of rapid diagnostic tests for detecting 4 molecular techniques is considerably low, typically in the range of 0.59-0.76 [6] , 0.66-0.88 [7] , or 0.57-0.71 [8] depending on the different populations and according to the distinct strategy used for pooling data. Therefore, although they can be rapidity performed outside of conventional clinical laboratories, the low accuracy does not enable efficient triage of COVID-19, leaving under-diagnosed up to one-third of subjects with SARS-CoV-2 infection [9] . With respect to body temperature assessment, several lines of evidence now attest that this approach is highly unreliable for screening due to a number of factors, including that elevated body temperature is not always present in patients with viral and/or SARS-CoV-2 infection, body temperature thresholds that are used for this purpose vary widely in the current scientific literature, body temperature differs according to the body district and may also be dramatically altered by environmental conditions (especially hot or cool temperatures), as well as be falsely low in patients taking antipyretic drugs, and finally, variability in the device used for its measurement [10] . Owing to these caveats, it is hence not surprising that a recent meta-analysis revealed that the overall predictive value of fever is around 80% and 50% in adult and pediatric populations, respectively [11] . The use of the so-called predictive scores has also been proposed for COVID-19 screening, though recent evidence underpins that their clinical efficiency seems rather modest (i.e., between 50-75%). [12, 13] . Taken together, the above data demonstrated that neither of these three potential approaches is foolproof, such that additional solutions should be identified and validated for screening patients with suspected COVID-19 upon healthcare facilities admissions, such as FebriDx, designed to rapidly distinguish bacterial vs. viral infections. FebriDx (Lumos diagnostics, Sarasota, FL, US) is a CE-approved, fast, selfcontained lateral flow-based POC immunoassay, specifically developed for differentiating viral from bacterial acute respiratory infections, as comprehensively described elsewhere [14] . Briefly [14] . We utilized an electronic search in Scopus and Medline (using the PubMed interface) with the keywords "FebriDX" AND "COVID-19" OR "SARS-CoV-2" within all search fields, without language or date (i.e., up to February 4, 2022) limits. An initial The electronic search conducted according to the aforementioned criteria enabled the identification of 7 articles after elimination of between-database duplicates. One of the identified items was not included in our analysis as it was a review article [16] , whilst one other article only reported data on MxA [17] . Thus, five studies, totalling 2309 patients, could be finally included in our analysis [18] [19] [20] [21] [22] , as summarized in Table 1 . Two included studies were published by the same team of authors, on different cohorts [18, 22] . Four studies were conducted in UK and one was conducted in Italy. In four studies, FebriDx was used for screening patients with suspected COVID-J o u r n a l P r e -p r o o f 19 at ED admission, whilst in the remaining study the test was more generally used for screening patients with suspected COVID-19 upon hospital admission. The sample ranged between 47 and 958 patients, with a generally old median age (four studies reported a median age >60 years) and greater prevalence of males (i.e., 51-68%). In two cases, the reference technique for diagnosing SARS-CoV-2 diagnosis was a laboratory- Rapid triage of patients with suspected COVID-19 is a key aspect for preventing ED overcrowding and delivering the best possible care to the patients [24] . Over two years after COVID-19 has been declared pandemic, a huge number of clinical laboratories are still facing enormous challenges to provide timely test results of SARS-CoV-2 testing and, even worse, cannot provide reliable solutions to facilitate fast and accurate diagnosis that is required in acute care and short-stay hospital units [25] . Several strategies have been proposed to overcome the main drawbacks (i.e., namely the J o u r n a l P r e -p r o o f almost unsuitable turnaround time) of molecular detection of SARS-CoV-2 RNA in these clinical settings, but most have failed to entry routine clinical practice for a variety of inherent reasons comprehensively reviewed elsewhere [26] . FebriDx is a single-use, portable test, which allows simultaneous qualitative assessment of two infective biomarkers (i.e., CRP and MxA), whose combined detection would enable to differentiate an acute viral infection from bacterial infections requiring antibiotics and from other non-infectious conditions. Therefore, its use or triaging patients with since it is the largest (n=856) and employed a rapid multiplex PCR testing for diagnosing SARSS-CoV-2 on NPS samples [22] . In fact, this real-world assessment of the device within an ED not only evidence a good diagnostic accuracy (0.81 sensitivity and 0.94 specificity, respectively) allowed to improve the number of patients moved from high-risk to lower-risk areas, but also enabled to shorten the length of stay in the ED (-15 min; 95%CI, -28 to -3 min), thus globally improving the triage efficiency. It is noteworthy that the excellent diagnostic performance of FebriDx emerged from this systematic analysis of current scientific literature has been estimated in cohorts of symptomatic patients, with high baseline risk and/or clinical suspicion of COVID-19. Therefore, translating such high diagnostic accuracy into a comparable efficiency for diagnosing any type of SARS-CoV-2 infection (thus including asymptomatic or mildly symptomatic cases) is unfeasible and misleading. This is especially true because the concentration of the two analytes simultaneously measured by FebriDx (i.e., CRP and MxA) is illness-dependent, especially that of CRP, whose concentration is directly correlated with severity of SARS-CoV-2 infection [28] , and is not significantly elevated in the vast majority of patients with mild or asymptomatic infections [29] . Likewise, Mataki et al. showed that the concentration of MxA is over 3fold lower in patients with mild SARS-CoV-2 infection compared to those with severe illness, with range of values (2.6-9.6 ng/mL) lying below the diagnostic cut-off of FebriDx (i.e., 40 ng/mL) [17] . At this point in time, it seems hence inadvisable to envisage FebriDx as a surrogate of NAATs or laboratory-based antigenic immunoassays, and its use should be limited to screening patients with highly suggestive signs and symptoms of COVID-19 in regions with high community circulation of SARS-CoV-2 and thus higher pre-test probability. Positive patients could then be prioritized for further confirmatory J o u r n a l P r e -p r o o f laboratory testing. Further studies will be needed to determine whether the excellent test accuracies reported in studies during the early stages of the pandemic will be replicated across different prevalence of SARS-CoV-2 infection, and especially in periods when SARS-CoV-2 might be circulating concomitantly with other respiratory viruses. The pooled evidence from the relatively limited number of studies published todate suggests that FebriDx retains a clinical value for rapid triage of patients with suspected COVID-19 upon hospital admission, especially in regions with high viral circulation in which the pre-test probability is high, as it would allow rapid screening and aid in overcoming the current shortage of reagents and personnel for performing NAATs. 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Assessing the potential value of a surrogate, point-of-care test for SARS-CoV-2 epidemic control Myxovirus resistance protein A in peripheral blood predicts supplemental oxygen need in COVID-19 Diagnostic accuracy of the FebriDx host response point-of-care test in patients hospitalised with suspected COVID-19 Utility of the FebriDx point-of-care assay in supporting a triage algorithm for medical admissions with possible COVID-19: an observational cohort study Utility of the FebriDx point-of-care test for rapid triage and identification of possible coronavirus disease 2019 (COVID-19) Use of the FebriDx point-of-care test for the exclusion of SARS-CoV-2 diagnosis in a population with acute respiratory infection during the second FebriDx host response point-of-care testing improves patient triage for COVID-19 in the emergency department The measurement of observer agreement for categorical data Point-of-care COVID-19 testing in the emergency department: current status and future prospects COVID-19 rapid diagnostics: practice review Editorial and Executive Summary: IFCC Interim Guidelines on Clinical Laboratory testing during the COVID-19 Pandemic Novel point-of-care biomarker combination tests to differentiate acute bacterial from viral respiratory tract infections to guide antibiotic prescribing: a systematic review The role of C-reactive protein in predicting the severity of COVID-19 disease: A systematic review Asymptomatic patients as a source of COVID-19 infections: A systematic review and metaanalysis Table 1. Summary of studies that investigated the diagnostic performance of FebriDx in patients with suspected coronavirus disease 2019 (COVID-19). Study Country Setting Date Study population Sample size Disease Prevalence COVID-19 diagnosis UK Screening of suspected COVID-19 at ED admission Median age, 70 (IQR, 52-81) years; 46% females 248 47.6% (95%CI, 41.2-54.0%) Lab-based RT-PCR assays on NPS UK Screening of suspected COVID-19 at ED admission 4-6.2%) Rapid RT-PCR assays on NPS Karim et al. 2021 UK Screening of suspected COVID-19 at ED admission Median age 67 (IQR, 53-77) years; 32% females 47 72.3% (95%CI, 57.4-84.4%) Lab-based RT-PCR assay on NPS and/or anti-SARS-CoV-2 antibodies Italy Screening of suspected COVID-19 at hospital admission Median age, 66 (IQR, 52-80) years; 38% females 200 68.0% (95%CI; 61.0-74.4%) Lab-based RT-PCR assays on NPS 2022 UK Screening of suspected COVID-19 at ED admission Median age 62 (IQR, 40-78) years; 49% females 856 17.9% (95%CI, 15.4-20.6%) Rapid multiplex PCR testing on NPS PCR, polymerase chain reaction; RT-PCR, real-time polymerase chain reaction