Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19
Cochrane COVID-19 Diagnostic Test Accuracy Group
(2022) Cochrane Database of Systematic Reviews, volume 5, issue 5
(Article)
Abstract
Background: COVID-19 illness is highly variable, ranging from infection with no symptoms through to pneumonia and life-threatening consequences. Symptoms such as fever, cough, or loss of sense of smell (anosmia) or taste (ageusia), can help flag early on if the disease is present. Such information could be used either to
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rule out COVID-19 disease, or to identify people who need to go for COVID-19 diagnostic tests. This is the second update of this review, which was first published in 2020. Objectives: To assess the diagnostic accuracy of signs and symptoms to determine if a person presenting in primary care or to hospital outpatient settings, such as the emergency department or dedicated COVID-19 clinics, has COVID-19. Search methods: We undertook electronic searches up to 10 June 2021 in the University of Bern living search database. In addition, we checked repositories of COVID-19 publications. We used artificial intelligence text analysis to conduct an initial classification of documents. We did not apply any language restrictions. Selection criteria: Studies were eligible if they included people with clinically suspected COVID-19, or recruited known cases with COVID-19 and also controls without COVID-19 from a single-gate cohort. Studies were eligible when they recruited people presenting to primary care or hospital outpatient settings. Studies that included people who contracted SARS-CoV-2 infection while admitted to hospital were not eligible. The minimum eligible sample size of studies was 10 participants. All signs and symptoms were eligible for this review, including individual signs and symptoms or combinations. We accepted a range of reference standards. Data collection and analysis: Pairs of review authors independently selected all studies, at both title and abstract, and full-text stage. They resolved any disagreements by discussion with a third review author. Two review authors independently extracted data and assessed risk of bias using the QUADAS-2 checklist, and resolved disagreements by discussion with a third review author. Analyses were restricted to prospective studies only. We presented sensitivity and specificity in paired forest plots, in receiver operating characteristic (ROC) space and in dumbbell plots. We estimated summary parameters using a bivariate random-effects meta-analysis whenever five or more primary prospective studies were available, and whenever heterogeneity across studies was deemed acceptable. Main results: We identified 90 studies; for this update we focused on the results of 42 prospective studies with 52,608 participants. Prevalence of COVID-19 disease varied from 3.7% to 60.6% with a median of 27.4%. Thirty-five studies were set in emergency departments or outpatient test centres (46,878 participants), three in primary care settings (1230 participants), two in a mixed population of in- and outpatients in a paediatric hospital setting (493 participants), and two overlapping studies in nursing homes (4007 participants). The studies did not clearly distinguish mild COVID-19 disease from COVID-19 pneumonia, so we present the results for both conditions together. Twelve studies had a high risk of bias for selection of participants because they used a high level of preselection to decide whether reverse transcription polymerase chain reaction (RT-PCR) testing was needed, or because they enrolled a non-consecutive sample, or because they excluded individuals while they were part of the study base. We rated 36 of the 42 studies as high risk of bias for the index tests because there was little or no detail on how, by whom and when, the symptoms were measured. For most studies, eligibility for testing was dependent on the local case definition and testing criteria that were in effect at the time of the study, meaning most people who were included in studies had already been referred to health services based on the symptoms that we are evaluating in this review. The applicability of the results of this review iteration improved in comparison with the previous reviews. This version has more studies of people presenting to ambulatory settings, which is where the majority of assessments for COVID-19 take place. Only three studies presented any data on children separately, and only one focused specifically on older adults. We found data on 96 symptoms or combinations of signs and symptoms. Evidence on individual signs as diagnostic tests was rarely reported, so this review reports mainly on the diagnostic value of symptoms. Results were highly variable across studies. Most had very low sensitivity and high specificity. RT-PCR was the most often used reference standard (40/42 studies). Only cough (11 studies) had a summary sensitivity above 50% (62.4%, 95% CI 50.6% to 72.9%)); its specificity was low (45.4%, 95% CI 33.5% to 57.9%)). Presence of fever had a sensitivity of 37.6% (95% CI 23.4% to 54.3%) and a specificity of 75.2% (95% CI 56.3% to 87.8%). The summary positive likelihood ratio of cough was 1.14 (95% CI 1.04 to 1.25) and that of fever 1.52 (95% CI 1.10 to 2.10). Sore throat had a summary positive likelihood ratio of 0.814 (95% CI 0.714 to 0.929), which means that its presence increases the probability of having an infectious disease other than COVID-19. Dyspnoea (12 studies) and fatigue (8 studies) had a sensitivity of 23.3% (95% CI 16.4% to 31.9%) and 40.2% (95% CI 19.4% to 65.1%) respectively. Their specificity was 75.7% (95% CI 65.2% to 83.9%) and 73.6% (95% CI 48.4% to 89.3%). The summary positive likelihood ratio of dyspnoea was 0.96 (95% CI 0.83 to 1.11) and that of fatigue 1.52 (95% CI 1.21 to 1.91), which means that the presence of fatigue slightly increases the probability of having COVID-19. Anosmia alone (7 studies), ageusia alone (5 studies), and anosmia or ageusia (6 studies) had summary sensitivities below 50% but summary specificities over 90%. Anosmia had a summary sensitivity of 26.4% (95% CI 13.8% to 44.6%) and a specificity of 94.2% (95% CI 90.6% to 96.5%). Ageusia had a summary sensitivity of 23.2% (95% CI 10.6% to 43.3%) and a specificity of 92.6% (95% CI 83.1% to 97.0%). Anosmia or ageusia had a summary sensitivity of 39.2% (95% CI 26.5% to 53.6%) and a specificity of 92.1% (95% CI 84.5% to 96.2%). The summary positive likelihood ratios of anosmia alone and anosmia or ageusia were 4.55 (95% CI 3.46 to 5.97) and 4.99 (95% CI 3.22 to 7.75) respectively, which is just below our arbitrary definition of a 'red flag', that is, a positive likelihood ratio of at least 5. The summary positive likelihood ratio of ageusia alone was 3.14 (95% CI 1.79 to 5.51). Twenty-four studies assessed combinations of different signs and symptoms, mostly combining olfactory symptoms. By combining symptoms with other information such as contact or travel history, age, gender, and a local recent case detection rate, some multivariable prediction scores reached a sensitivity as high as 90%. Authors' conclusions: Most individual symptoms included in this review have poor diagnostic accuracy. Neither absence nor presence of symptoms are accurate enough to rule in or rule out the disease. The presence of anosmia or ageusia may be useful as a red flag for the presence of COVID-19. The presence of cough also supports further testing. There is currently no evidence to support further testing with PCR in any individuals presenting only with upper respiratory symptoms such as sore throat, coryza or rhinorrhoea. Combinations of symptoms with other readily available information such as contact or travel history, or the local recent case detection rate may prove more useful and should be further investigated in an unselected population presenting to primary care or hospital outpatient settings. The diagnostic accuracy of symptoms for COVID-19 is moderate to low and any testing strategy using symptoms as selection mechanism will result in both large numbers of missed cases and large numbers of people requiring testing. Which one of these is minimised, is determined by the goal of COVID-19 testing strategies, that is, controlling the epidemic by isolating every possible case versus identifying those with clinically important disease so that they can be monitored or treated to optimise their prognosis. The former will require a testing strategy that uses very few symptoms as entry criterion for testing, the latter could focus on more specific symptoms such as fever and anosmia.
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Keywords: Aged, Ageusia/complications, Anosmia/diagnosis, Artificial Intelligence, COVID-19 Testing, COVID-19/diagnosis, Child, Cough/etiology, Dyspnea, Fatigue/etiology, Fever/diagnosis, Hospitals, Humans, Outpatients, Pharyngitis, Primary Health Care, Prospective Studies, SARS-CoV-2, Sensitivity and Specificity, Case Reports, Journal Article, Meta-Analysis, Review, Research Support, Non-U.S. Gov't
ISSN: 1465-1858
Publisher: John Wiley and Sons Ltd
Note: Funding Information: Funded by Mass CPR Grant and the Massachusetts General Hospital Executive Committee on Research (Carney Family Foundation Award to CAS and Steve and Deborah Gorlin Research Scholars Award to RPW). Funding Information: Funding: supported by the Dutch Ministry of Health, Welfare, and sport Funding Information: Funding: Emergency Response Project for New Coronavirus of Science and Technology Department of Sichuan Provincial, Grant/Award Numbers: 2020YFS0005, 2020YFS0009; Special Funds for COVID-19 Prevention and Control of West China Hospital of Sichuan University, Grant/Award Number: HX-2019-nCoV-068; Science and Technology Benefit People Project of Chengdu Municipality, Grant/ Award Number: 2016-HM02-00099-SF Funding Information: Funding: supported by the National Institute of Allergy and Infectious Diseases (R01 AI135114 to D.T.L.) and the National Heart, Lung, and Blood Institute (K08 HL13650 to R.U.S.) of the National Institutes of Health; and the Centers for Disease Control and Prevention (5U01CK000555-02 to M.H.S. and 5U01CK000538-03 to M.H.S. and L.T.K.) Funding Information: Funding: National Natural Science Foundation of China Funding Information: Funding: supported by the National Center for Advancing Translational Sciences, the National Heart Lung Blood Institute, National Institute of Allergy and Infectious Diseases, the Chan Zuckerberg Biohub, the Chan Zuckerberg Initiative Funding Information: + D+I 2013-2016) and co financed by the European Development Regional Fund Funding Information: Funding: Supported by the National Heart, Lung, and Blood Institute (5K08HL143183 to L.Y.), the Cystic Fibrosis Foundation (YONKER18Q0 to L.Y.), the National Institute of Child Health and Human Development (K08 HD094638 [to A.N.] and R01HD100022 [to A.E.]), Mark and Lisa Schwartz (to J.L.), the National Institute of Diabetes and Digestive and Kidney Diseases (DK039773, DK072381 [to J.B.] and DK104344 [to A.F.]), the National Institute of Allergy and Infectious Disease (K24AI141036 to I.B.), the Centers for Disease Control and Prevention (U01CK000490 to E.R.), and the Department of Pediatrics and the Department of Obstetrics/Gynecology at Massachusetts General Hospital (to L.Y. and A.E.) Funding Information: Funding: supported by the Mexican Institute of Social Security Funding Information: Funding: supported by the Indian Council of Medical Research-National Institute of Epidemiology (ICMR-NIE) Funding Information: Funding: supported by the Key Discipline of Pudong Area, Shangai Funding Information: Funding: FM was funded by an Alberta Health Services Chair in Cardiovascular Outcomes Research; project was funded by the Alberta Strategy for Patient Oriented Research Support Unit Funding Information: Funding: supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award UL1TR001412 to the University at Buffalo Funding Information: Members of the Cochrane COVID-19 Diagnostic Test Accuracy Review Group include the following. The project team (Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Leeflang MMG, Spijker R, Hooft L, Van den Bruel A, McInnes MDF, Emperador D, Dittrich S) The systematic review teams for each review: molecular, antigen, and antibody tests (Adriano A, Beese S, Dretzke J, Ferrante di Ruffano L, Harris I, Price M, Taylor-Phillips S); signs and symptoms (Struyf T, Domen J, Horn S, Lannoy V, Wickramasinghe D, Janssens S, Tans A); routine laboratory markers (Yang B, Langendam M, Ochodo E, Guleid F, Holtman G, Verbakel J, Wang J, Stegeman I); imaging tests (Salameh JP, McGrath TA, van der Pol CB, Frank RA, Prager R, Hare SS, Dennie C, Jenniskens K, Korevaar DA, Cohen JF, Van de Wijgert J, Damen JAAG, Wang J). The wider team of systematic reviewers from University of Birmingham, UK who assisted with title and abstract screening across the entire suite of reviews for the diagnosis of COVID-19 (Agarwal R, Baldwin S, Berhane S, Herd C, Kristunas C, Quinn L, Scholefield B): see Deeks 2020a; Dinnes 2021; Islam 2021; Stegeman 2020). The project team (Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Leeflang MMG, Spijker R, Hooft L, Van den Bruel A, McInnes MDF, Emperador D, Dittrich S) The systematic review teams for each review: molecular, antigen, and antibody tests (Adriano A, Beese S, Dretzke J, Ferrante di Ruffano L, Harris I, Price M, Taylor-Phillips S); signs and symptoms (Struyf T, Domen J, Horn S, Lannoy V, Wickramasinghe D, Janssens S, Tans A); routine laboratory markers (Yang B, Langendam M, Ochodo E, Guleid F, Holtman G, Verbakel J, Wang J, Stegeman I); imaging tests (Salameh JP, McGrath TA, van der Pol CB, Frank RA, Prager R, Hare SS, Dennie C, Jenniskens K, Korevaar DA, Cohen JF, Van de Wijgert J, Damen JAAG, Wang J). The wider team of systematic reviewers from University of Birmingham, UK who assisted with title and abstract screening across the entire suite of reviews for the diagnosis of COVID-19 (Agarwal R, Baldwin S, Berhane S, Herd C, Kristunas C, Quinn L, Scholefield B): see Deeks 2020a; Dinnes 2021; Islam 2021; Stegeman 2020). Jonathan Deeks is a UK National Institute for Health Research (NIHR) Senior Investigator Emeritus. Yemisi Takwoingi is supported by a NIHR Postdoctoral Fellowship. Jonathan Deeks, Jacqueline Dinnes, Yemisi Takwoingi, Clare Davenport and Malcolm Price are supported by the NIHR Birmingham Biomedical Research Centre. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. We thank Dr Jane Cunningham (World Health Organization) for participation in technical discussions and comments on the review. Cochrane Infectious Diseases supported the review authors in the development of this second update. The Cochrane Infectious Diseases' editorial base is funded by UK aid from the UK government for the benefit of low- and middle-income countries (project number 300342-104). The views expressed do not necessarily reflect the UK government’s official policies. The following people conducted the editorial process for this review update. Sign-off Editor (final editorial decision): Michael Brown, Michigan State University College of Human Medicine, USA Managing Editor (selected peer reviewers, collated peer-reviewer comments, provided editorial guidance to authors, edited the update): Joey Kwong, Cochrane Evidence Production & Methods Directorate Editorial Assistant (conducted editorial policy checks and supported editorial team): Leticia Rodrigues, Cochrane Evidence Production & Methods Directorate Copy Editor (copy-editing and production): Denise Mitchell, Cochrane Copy Edit Support Peer-reviewers (provided comments and recommended an editorial decision): Brendan Delaney, Imperial College London (clinical review); Lao-Tzu Allan-Blitz, Division Global Health Equity: Department of Medicine, Brigham and Women's Hospital Department of Pediatrics, Boston Children's Hospital (clinical review); Paul Garner, Liverpool School of Tropical Medicine (clinical review)*; Jenny Negus (consumer review); Lynda Ware, Cochrane UK (summary versions review); Gianni Virgili and Tanya Walsh, Cochrane Diagnostic Test Accuracy Reviews Editorial Team (methods review); Robin Featherstone, Cochrane Evidence Production & Methods Directorate (search review). *Paul Garner is a member of Cochrane Infectious Diseases and provided peer-review comments on this update, but was not otherwise involved in the editorial process or decision making. One additional peer reviewer provided clinical peer review but chose not to be publicly acknowledged. Sign-off Editor (final editorial decision): Michael Brown, Michigan State University College of Human Medicine, USA Managing Editor (selected peer reviewers, collated peer-reviewer comments, provided editorial guidance to authors, edited the update): Joey Kwong, Cochrane Evidence Production & Methods Directorate Editorial Assistant (conducted editorial policy checks and supported editorial team): Leticia Rodrigues, Cochrane Evidence Production & Methods Directorate Copy Editor (copy-editing and production): Denise Mitchell, Cochrane Copy Edit Support Peer-reviewers (provided comments and recommended an editorial decision): Brendan Delaney, Imperial College London (clinical review); Lao-Tzu Allan-Blitz, Division Global Health Equity: Department of Medicine, Brigham and Women's Hospital Department of Pediatrics, Boston Children's Hospital (clinical review); Paul Garner, Liverpool School of Tropical Medicine (clinical review)*; Jenny Negus (consumer review); Lynda Ware, Cochrane UK (summary versions review); Gianni Virgili and Tanya Walsh, Cochrane Diagnostic Test Accuracy Reviews Editorial Team (methods review); Robin Featherstone, Cochrane Evidence Production & Methods Directorate (search review). *Paul Garner is a member of Cochrane Infectious Diseases and provided peer-review comments on this update, but was not otherwise involved in the editorial process or decision making. One additional peer reviewer provided clinical peer review but chose not to be publicly acknowledged. Funding Information: Funding: grant for International Health Research from the Ministry of Health Labor and Welfare of Japan (grant no. 20A2003D) Funding Information: Funding: supported by grants from the PLA Science and Technology Project (14CXZ005, AWS15J004, 16BJZ19), National Key R&D Program of China (2019 yearsFF0302300), Construction Project of Key Disciplines in the 13th Five-Year Plan of the PLA (Traumatic Surgery in the Battlefield, 2019-126, 2019-513), Beijing Science and Technology New Star Project (XX2018019/Z181100006218028), the PLA General Hospital Science and technology Project (2019XXJSYX20, 2018XXFC-20, ZH19016) Funding Information: Funding: the municipal health department of São Caetano do Sul funded the establishment and implementation of the platform. Plus award from FAPESP (2018/14389-0) and the UK Medical Research Council (MR/S0195/1) to the Brazil-UK Centre for Arbovirus Discovery Funding Information: Funding: the CoV-19 POC trial was funded by University of Southampton and University Hospital Southampton NHS Foundation Trust. NJB is supported by a National Institute of Health Research (NIHR) Clinical Lecturer post. TWC is supported by a NIHR Fellowship (PDF 2016-09-061). Funding Information: Funding: supported through cooperative agreements funded by the US Centers for Disease Control and Prevention and, at the University of Pittsburgh, by infrastructure funding from the National Institutes of Health (UL1 TR001857). Funding Information: Cochrane Infectious Diseases supported the review authors in the development of this second update. The Cochrane Infectious Diseases' editorial base is funded by UK aid from the UK government for the benefit of low-and middle-income countries (project number 300342-104). The views expressed do not necessarily reflect the UK government’s official policies. Funding Information: Funding: supported by the National Natural Science Foundation of China [Grants 81874149, 81974456, and 81530024]; the Clinical Research Physician Program of Tongji Medical College, Huazhong University of Science and Technology [Grant 5001540075]; SARS-CoV-2 Pneumonia Emergency Technology Public Relations Project [2020FCA009] Funding Information: Conflicts of interest: DB and BV declare having received past personal fees and grant from Qiagen (Hilden, Germany) Funded by the AP-HP (Assistance Publique – Hôpitaux de Paris). This study was supported by Qiagen in the form of a grant funding the data management of the RespiFast2 study targeting to assess the impact of respiratory viruses and of discounted equipment and consumables in the context of the COVID-19 outbreak. Funding Information: Jonathan Deeks is a UK National Institute for Health Research (NIHR) Senior Investigator Emeritus. Yemisi Takwoingi is supported by a NIHR Postdoctoral Fellowship. Jonathan Deeks, Jacqueline Dinnes, Yemisi Takwoingi, Clare Davenport and Malcolm Price are supported by the NIHR Birmingham Biomedical Research Centre. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding Information: Funding: supported by the following grants from Singapore Ministry of Health’s National Medical Research Council: collaborative Solutions Targeting Antimicrobial Resistance Threats in Health Systems (CoSTAR-HS) [NMRC CGAug16C005], NMRC Clinician Scientist Award [MOH-000276] and NMRC Clinician Scientist Individual Research Grant [MOH-CIRG18nov-0006]. Publisher Copyright: Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.
(Peer reviewed)