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      Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID‐19

      systematic-review

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          Abstract

          Background

          The clinical implications of SARS‐CoV‐2 infection are highly variable. Some people with SARS‐CoV‐2 infection remain asymptomatic, whilst the infection can cause mild to moderate COVID‐19 and COVID‐19 pneumonia in others. This can lead to some people requiring intensive care support and, in some cases, to death, especially in older adults. Symptoms such as fever, cough, or loss of smell or taste, and signs such as oxygen saturation are the first and most readily available diagnostic information. Such information could be used to either rule out COVID‐19, or select patients for further testing. This is an update of this review, the first version of which published in July 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

          For this review iteration we undertook electronic searches up to 15 July 2020 in the Cochrane COVID‐19 Study Register and the University of Bern living search database. In addition, we checked repositories of COVID‐19 publications. We did not apply any language restrictions.

          Selection criteria

          Studies were eligible if they included patients with clinically suspected COVID‐19, or if they recruited known cases with COVID‐19 and controls without COVID‐19. Studies were eligible when they recruited patients presenting to primary care or hospital outpatient settings. Studies in hospitalised patients were only included if symptoms and signs were recorded on admission or at presentation. Studies including patients 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 stage and full‐text stage. They resolved any disagreements by discussion with a third review author. Two review authors independently extracted data and resolved disagreements by discussion with a third review author. Two review authors independently assessed risk of bias using the Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS‐2) checklist. We presented sensitivity and specificity in paired forest plots, in receiver operating characteristic space and in dumbbell plots. We estimated summary parameters using a bivariate random‐effects meta‐analysis whenever five or more primary studies were available, and whenever heterogeneity across studies was deemed acceptable.

          Main results

          We identified 44 studies including 26,884 participants in total. Prevalence of COVID‐19 varied from 3% to 71% with a median of 21%. There were three studies from primary care settings (1824 participants), nine studies from outpatient testing centres (10,717 participants), 12 studies performed in hospital outpatient wards (5061 participants), seven studies in hospitalised patients (1048 participants), 10 studies in the emergency department (3173 participants), and three studies in which the setting was not specified (5061 participants). The studies did not clearly distinguish mild from severe COVID‐19, so we present the results for all disease severities together.

          Fifteen studies had a high risk of bias for selection of participants because inclusion in the studies depended on the applicable testing and referral protocols, which included many of the signs and symptoms under study in this review. This may have especially influenced the sensitivity of those features used in referral protocols, such as fever and cough. Five studies only included participants with pneumonia on imaging, suggesting that this is a highly selected population. In an additional 12 studies, we were unable to assess the risk for selection bias. This makes it very difficult to judge the validity of the diagnostic accuracy of the signs and symptoms from these included studies.

          The applicability of the results of this review update improved in comparison with the original review. A greater proportion of studies included participants who presented to outpatient settings, which is where the majority of clinical assessments for COVID‐19 take place. However, still none of the studies presented any data on children separately, and only one focused specifically on older adults.

          We found data on 84 signs and symptoms. Results were highly variable across studies. Most had very low sensitivity and high specificity. Only cough (25 studies) and fever (7 studies) had a pooled sensitivity of at least 50% but specificities were moderate to low. Cough had a sensitivity of 67.4% (95% confidence interval (CI) 59.8% to 74.1%) and specificity of 35.0% (95% CI 28.7% to 41.9%). Fever had a sensitivity of 53.8% (95% CI 35.0% to 71.7%) and a specificity of 67.4% (95% CI 53.3% to 78.9%). The pooled positive likelihood ratio of cough was only 1.04 (95% CI 0.97 to 1.11) and that of fever 1.65 (95% CI 1.41 to 1.93).

          Anosmia alone (11 studies), ageusia alone (6 studies), and anosmia or ageusia (6 studies) had sensitivities below 50% but specificities over 90%. Anosmia had a pooled sensitivity of 28.0% (95% CI 17.7% to 41.3%) and a specificity of 93.4% (95% CI 88.3% to 96.4%). Ageusia had a pooled sensitivity of 24.8% (95% CI 12.4% to 43.5%) and a specificity of 91.4% (95% CI 81.3% to 96.3%). Anosmia or ageusia had a pooled sensitivity of 41.0% (95% CI 27.0% to 56.6%) and a specificity of 90.5% (95% CI 81.2% to 95.4%). The pooled positive likelihood ratios of anosmia alone and anosmia or ageusia were 4.25 (95% CI 3.17 to 5.71) and 4.31 (95% CI 3.00 to 6.18) respectively, which is just below our arbitrary definition of a 'red flag', that is, a positive likelihood ratio of at least 5. The pooled positive likelihood ratio of ageusia alone was only 2.88 (95% CI 2.02 to 4.09).

          Only two studies assessed combinations of different signs and symptoms, mostly combining fever and cough with other symptoms. These combinations had a specificity above 80%, but at the cost of very low sensitivity (< 30%).

          Authors' conclusions

          The majority of individual signs and symptoms included in this review appear to have very poor diagnostic accuracy, although this should be interpreted in the context of selection bias and heterogeneity between studies. Based on currently available data, neither absence nor presence of signs or symptoms are accurate enough to rule in or rule out COVID‐19. The presence of anosmia or ageusia may be useful as a red flag for COVID‐19. The presence of fever or cough, given their high sensitivities, may also be useful to identify people for further testing.

          Prospective studies in an unselected population presenting to primary care or hospital outpatient settings, examining combinations of signs and symptoms to evaluate the syndromic presentation of COVID‐19, are still urgently needed. Results from such studies could inform subsequent management decisions.

          Plain language summary

          Can symptoms and medical examination accurately diagnose COVID‐19?

          COVID‐19 affects many organs of the body, so people with COVID‐19 may have a wide spectrum of symptoms. Symptoms and signs of the illness may be important to help them and the healthcare staff they come into contact with know whether they have the disease.

          Symptoms: people with mild COVID‐19 might experience cough, sore throat, high temperature, diarrhoea, headache, muscle or joint pain, fatigue, and loss or disturbance of sense of smell and taste.

          Signs are obtained by clinical examination. Signs of COVID‐19 examined in this review include lung sounds, blood pressure, blood oxygen level and heart rate.

          Often, people with mild symptoms consult their doctor (general practitioner). People with more severe symptoms might visit a hospital outpatient or emergency department. Depending on the results of a clinical examination, patients may be sent home to isolate, may receive further tests or be hospitalised.

          Why is accurate diagnosis important?

          Accurate diagnosis ensures that people take measures to avoid transmitting the disease and receive appropriate care. This is important for individuals as it reduces harm and it saves time and resources.

          What did we want to find out?

          We wanted to know how accurate diagnosis of COVID‐19 is in a primary care or hospital setting, based on symptoms and signs from medical examination.

          What did we do?

          We searched for studies that assessed the accuracy of symptoms and signs to diagnose COVID‐19. Studies had to be conducted in primary care or hospital outpatient settings only. Studies of people in hospital were only included if symptoms and signs were recorded when they were admitted to the hospital.

          The included studies

          We found 44 relevant studies with 26,884 participants. The studies assessed 84 separate signs and symptoms, and some assessed combinations of signs and symptoms. Three studies were conducted in primary care (1824 participants), nine in specialist COVID‐19 testing clinics (10,717 participants), 12 studies in hospital outpatient settings (5061 participants), seven studies in hospitalised patients (1048 participants), 10 studies in the emergency department (3173 participants), and in three studies the setting was not specified (5061 participants). No studies focused specifically on children, and only one focused on older adults.

          Main results

          The studies did not clearly distinguish between mild and severe COVID‐19, so we present the results for mild, moderate and severe disease together.

          The symptoms most frequently studied were cough and fever. In our studies, on average 21% of the participants had COVID‐19, which means in a group of 1000 people, around 210 would have COVID‐19.

          According to the studies in our review, in the same 1000 people, around 655 people would have a cough. Of these, 142 would actually have COVID‐19. Of the 345 who do not have a cough, 68 would have COVID‐19.

          In the same 1000 people, around 371 people would have a fever. Of these, 113 would actually have COVID‐19. Of the 629 patients without fever, 97 would have COVID‐19.

          The loss of sense of smell or taste also substantially increase the likelihood of COVID‐19 when they are present. For example, in a population where 2% of the people have COVID‐19, having either loss of smell or loss of taste would increase a persons’ likelihood of having COVID‐19 to 8%.

          How reliable are the results?

          The accuracy of individual symptoms and signs varied widely across studies. Moreover, the studies selected participants in a way that meant the accuracy of tests based on symptoms and signs may be uncertain.

          Conclusions

          Most studies were conducted in hospital settings, so the results may not be entirely representative of primary care settings. The results do not apply to children or older adults specifically, and do not clearly differentiate between disease severities.

          The results suggest that a single symptom or sign included in this review cannot accurately diagnose COVID‐19. However, the presence of loss of taste or smell may serve as a red flag for the presence of the disease. The presence of high temperature or cough may also be useful to identify people who might have COVID‐19. These symptoms may be useful to prompt further testing when they are present.

          Further research is needed to investigate combinations of symptoms and signs; and testing unselected populations, in primary care settings and in children and older adults.

          How up to date is this review?

          For this update of the review, the authors searched for studies published from January to July 2020.

          Related collections

          Most cited references66

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

          In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.
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            STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies

            Incomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting Diagnostic Accuracy (STARD) statement was developed. Here we present STARD 2015, an updated list of 30 essential items that should be included in every report of a diagnostic accuracy study. This update incorporates recent evidence about sources of bias and variability in diagnostic accuracy and is intended to facilitate the use of STARD. As such, STARD 2015 may help to improve completeness and transparency in reporting of diagnostic accuracy studies.
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              Emerging 2019 Novel Coronavirus (2019-nCoV) Pneumonia

              Background The chest CT findings of patients with 2019 Novel Coronavirus (2019-nCoV) pneumonia have not previously been described in detail. Purpose To investigate the clinical, laboratory, and imaging findings of emerging 2019-nCoV pneumonia in humans. Materials and Methods Fifty-one patients (25 men and 26 women; age range 16–76 years) with laboratory-confirmed 2019-nCoV infection by using real-time reverse transcription polymerase chain reaction underwent thin-section CT. The imaging findings, clinical data, and laboratory data were evaluated. Results Fifty of 51 patients (98%) had a history of contact with individuals from the endemic center in Wuhan, China. Fever (49 of 51, 96%) and cough (24 of 51, 47%) were the most common symptoms. Most patients had a normal white blood cell count (37 of 51, 73%), neutrophil count (44 of 51, 86%), and either normal (17 of 51, 35%) or reduced (33 of 51, 65%) lymphocyte count. CT images showed pure ground-glass opacity (GGO) in 39 of 51 (77%) patients and GGO with reticular and/or interlobular septal thickening in 38 of 51 (75%) patients. GGO with consolidation was present in 30 of 51 (59%) patients, and pure consolidation was present in 28 of 51 (55%) patients. Forty-four of 51 (86%) patients had bilateral lung involvement, while 41 of 51 (80%) involved the posterior part of the lungs and 44 of 51 (86%) were peripheral. There were more consolidated lung lesions in patients 5 days or more from disease onset to CT scan versus 4 days or fewer (431 of 712 lesions vs 129 of 612 lesions; P < .001). Patients older than 50 years had more consolidated lung lesions than did those aged 50 years or younger (212 of 470 vs 198 of 854; P < .001). Follow-up CT in 13 patients showed improvement in seven (54%) patients and progression in four (31%) patients. Conclusion Patients with fever and/or cough and with conspicuous ground-glass opacity lesions in the peripheral and posterior lungs on CT images, combined with normal or decreased white blood cells and a history of epidemic exposure, are highly suspected of having 2019 Novel Coronavirus (2019-nCoV) pneumonia. © RSNA, 2020
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                Author and article information

                Journal
                Cochrane Database Syst Rev
                Cochrane Database Syst Rev
                14651858
                10.1002/14651858
                The Cochrane Database of Systematic Reviews
                John Wiley & Sons, Ltd (Chichester, UK )
                1469-493X
                23 February 2021
                2021
                23 February 2021
                : 2021
                : 2
                : CD013665
                Affiliations
                deptDepartment of Public Health and Primary Care KU Leuven LeuvenBelgium
                deptTest Evaluation Research Group, Institute of Applied Health Research University of Birmingham BirminghamUK
                deptTest Evaluation Research Group, Institute of Applied Health Research University of Birmingham Birmingham UK
                deptEpidemiology and Data Science Amsterdam University Medical Centers, University of Amsterdam AmsterdamNetherlands
                deptMedical Library Amsterdam UMC, University of Amsterdam, Amsterdam Public Health AmsterdamNetherlands
                deptCochrane Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University Utrecht Netherlands
                FIND GenevaSwitzerland
                De Wijkpraktijk AntwerpBelgium
                deptNIHR Birmingham Biomedical Research Centre University Hospitals Birmingham NHS Foundation Trust and University of Birmingham BirminghamUK
                deptBiomarker and Test Evaluation Programme (BiTE) Amsterdam UMC, University of Amsterdam AmsterdamNetherlands
                deptCochrane Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University UtrechtNetherlands
                Article
                CD013665.pub2 CD013665
                10.1002/14651858.CD013665.pub2
                8407425
                33620086
                2968787f-7a12-4c3d-9c20-443b8f10ce9d
                Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

                This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial Licence, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Categories
                Child health
                Diagnosis
                Infectious disease
                COVID-19

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