key: cord-0741759-p196javw
authors: Vihta, Karina-Doris; Pouwels, Koen B; Peto, Tim; Pritchard, Emma; Eyre, David W; House, Thomas; Gethings, Owen; Studley, Ruth; Rourke, Emma; Cook, Duncan; Diamond, Ian; Crook, Derrick; Matthews, Philippa C; Stoesser, Nicole; Walker, Ann Sarah
title: Symptoms and SARS-CoV-2 positivity in the general population in the UK
date: 2021-11-08
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab945
sha: 8aaa581ebcb5da7c58828fd5d6107547f8c7dd81
doc_id: 741759
cord_uid: p196javw

BACKGROUND: ‘Classic’ symptoms (cough, fever, loss of taste/smell) prompt SARS-CoV-2 PCR-testing in the UK. Studies have assessed the ability of different symptoms to identify infection, but few have compared symptoms over time (reflecting variants) and by vaccination status. METHODS: Using the COVID-19 Infection Survey, sampling households across the UK, we compared symptoms in PCR-positives vs. PCR-negatives, evaluating sensitivity of combinations of 12 symptoms (percentage symptomatic PCR-positives reporting specific symptoms) and tests per case (TPC) (PCR-positives or PCR-negatives reporting specific symptoms/ PCR-positives reporting specific symptoms). RESULTS: Between April 2020 and August 2021, 27,869 SARS-CoV-2 PCR-positive episodes occurred in 27,692 participants (median 42 years), of whom 13,427 (48%) self-reported symptoms (“symptomatic PCR-positives”). The comparator comprised 3,806,692 test-negative visits (457,215 participants); 130,612 (3%) self-reported symptoms (“symptomatic PCR-negatives”). Symptom reporting in PCR-positives varied by age, sex, and ethnicity, and over time, reflecting changes in prevalence of viral variants, incidental changes (e.g. seasonal pathogens (with sore throat increasing in PCR-positives and PCR-negatives from April 2021), schools re-opening) and vaccination roll-out. After May-2021 when Delta emerged, headache and fever substantially increased in PCR-positives, but not PCR-negatives. Sensitivity of symptom-based detection increased from 74% using ‘classic’ symptoms, to 81% adding fatigue/weakness, and 90% including all eight additional symptoms. However, this increased TPC from 4.6 to 5.3 to 8.7. CONCLUSIONS: Expanded symptom combinations may provide modest benefits for sensitivity of PCR-based case detection, but this will vary between settings and over time, and increases tests/case. Large-scale changes to targeted PCR-testing approaches require careful evaluation given substantial resource and infrastructure implications.

Symptomatic SARS-CoV-2 infection is associated with higher viral loads [1] , and higher viral loads with infectivity and transmission [2] , while infections that remain asymptomatic [3, 4] have lower individual consequences. Resource constraints prevent universal testing, so testing strategies are usually targeted to the most predictive symptoms and/or contacts of known positives. Currently, four "classic" symptoms trigger PCR-based community testing in the UK, loss/change of smell/taste, fever, and/or a new, continuous cough. In the US, the Centers for Disease Control (CDC) advises testing for any of fever or chills, cough, shortness of breath/difficulty breathing, new loss of taste/smell, fatigue, muscle or body aches, headache, sore throat, congestion/runny nose, nausea/vomiting, or diarrhoea.

As testing policies depend on symptoms, understanding their predictive value in the context of seasonality, changing prevalence of different variants [1] , and vaccination [5] is essential. Most studies to date have restricted to those hospitalised or seeking healthcare, who do not represent most infections [6] . Three recent UK community-based studies suggested that sensitivity could be increased by 10-20% by extending the "classic" symptoms. REACT [7] recommended adding headache, muscle aches, chills and appetite loss, depending on age. ZOE [8] included different symptoms depending on age, sex, BMI and working in healthcare. VirusWatch[9] added feeling feverish, headache, muscle aches, loss of appetite or chills, but at a cost of increasing numbers eligible for testing 2-3 fold and tests per (symptomatic PCR-positive) case (TPC) to 7-fold. However, these studies were mainly before widespread vaccination, whilst Alpha dominated. Although ZOE found no evidence that symptoms varied between wild type and Alpha [10] , with Delta, ZOE identified headache, sore throat and runny nose/sneezing as non-classic symptoms most commonly occurring in fully, partially and unvaccinated PCR-positives [11] .

A c c e p t e d M a n u s c r i p t 7 7 We therefore used a large representative community-based UK survey to investigate symptoms over time in PCR-positives and PCR-negatives, also evaluating the impact of age, ethnicity, cycle threshold (Ct) value, vaccination status and PCR gene profile (a proxy for variant).

The Office for National Statistics (ONS) COVID-19 Infection Survey [12] (ISRCTN21086382, https://www.ndm.ox.ac.uk/covid-19/covid-19-infection-survey/protocol-and-information-sheets) continuously randomly selects private households from address lists and previous surveys. Having obtained verbal agreement, each household is visited by a study worker, and written informed consent obtained for individuals aged 2y (from parents/carers for those 2-15y, those 10-15y providing written assent). At the first visit, participants may consent for optional follow-up visits every week for the next month, then monthly thereafter. At each visit, participants provide a nose and throat self-swab and answer questions about behaviours, work, vaccination uptake and twelve specific symptoms in the last 7 days (https://www.ndm.ox.ac.uk/covid-19/covid-19-infectionsurvey/case-record-forms): loss of taste, loss of smell, fever, cough, headache, tiredness/weakness (denoted fatigue/weakness), muscle ache (denoted muscle ache/myalgia), abdominal pain, diarrhoea, nausea or vomiting, shortness of breath and sore throat; plus a general question about any symptoms participants considered COVID-19-related (combined with specific symptoms as any evidence of symptoms).

Swabs are tested at national laboratories using the ThermoFisher TaqPath PCR assay (3 targets: ORF1ab, nucleocapsid (N), and spike protein (S)). If N and/or ORF1ab genes are detected, samples are called positive; the S-gene can accompany other genes, but does not count as positive alone.

We included the first positive study test in each PCR-positive "episode", defining re-infections (arbitrarily) as occurring 120 days after an index positive with a preceding negative test, or after 4 A c c e p t e d M a n u s c r i p t 8 8 consecutive negative tests [5] . Each positive episode was characterised by its minimum Ct value (reflecting maximum viral load) and by viral variant as wild-type/Delta if the S-gene was ever detected (by definition, with N/ORF1ab/both), as Alpha-compatible if positive at least once for ORF1ab+N, otherwise "other" (N-only/ORF1ab-only) (Fig.S1 ). Symptom presence included reports at any visit (PCR-positive/PCR-negative/failed) within [0,+35] days of the first PCR-positive.

The comparator was visits with negative PCR tests, excluding visits with symptoms related to ongoing COVID-19 (and long COVID), with high probability of undetected COVID-19, and where symptoms were likely associated with recent vaccination (Supplementary Methods, Fig.S2 ).

Primary analyses restricted to positive episodes vs. negative visits with evidence of any symptoms ("symptomatic PCR-positives" vs "symptomatic PCR-negatives"), because this population is targeted for testing. We considered all symptomatic PCR-positives, and subgroups defined by Ct, viral variant, A c c e p t e d M a n u s c r i p t 10 10

Fatigue/weakness, cough, and headache were the most frequently reported symptoms in PCRpositives (54%, 54%, 52% of symptomatic PCR-positives; Fig.1 ). However, headache and cough were also frequent among PCR-negatives, as was sore throat (23%, 22%, 22%, respectively; Fig.1 ). Loss of taste/smell were the most specific symptoms for SARS-CoV-2 positivity (reported in 33%/33% PCRpositives, vs. 2%/2% PCR-negatives). In PCR-positives, loss of taste or smell were commonly coreported, as were gastrointestinal symptoms, and headache/myalgia/fatigue. Symptom co-reporting in symptomatic PCR-positives was broadly similar regardless of Ct, variant, vaccination status or age ( Fig.S3 ). Symptom clustering was broadly similar in PCR-negatives, except cough and sore throat were more commonly co-reported.

In symptomatic PCR-positives, symptomatology varied by viral variant ( Fig.1; unadjusted) . A smaller percentage of symptomatic PCR-positives reported loss of taste/smell for Alpha-compatible (31%/28%) than wild-type (38%/36%) or Delta-compatible (38%/39%) infection (p<0.0001).

Fever/headache/sore throat had the largest difference between symptoms reported for Alphacompatible (37%/56%/38%) and Delta-compatible (46%/62%/50%) infection (p<0.0001). Cough and fatigue/weakness had the largest differences between wild-type (50%/50%) vs Alpha-compatible (61%/61%) or Delta-compatible (64%/60%) infection (p<0.0001). In general, specific symptoms were reported slightly more in symptomatic PCR-positives 14d from second vaccination versus those unvaccinated or 21d from first vaccination (Fig.1) .

A c c e p t e d M a n u s c r i p t 11 11 Symptomatology over calendar time Adjusting for age, sex and ethnicity, the probability of reporting any symptoms amongst PCRpositives was reasonably stable after August-2020 given changes in incidence and sample size (Fig.2, top panels, Table S4 Christmas, and from early April-2021 when schools had reopened [13] . The winter months saw particular increases in gastrointestinal symptoms, fatigue/weakness, myalgia and headache in symptomatic PCR-negatives, consistent with the presence of other seasonal pathogens.

All symptoms showed marked variation across age in both PCR-positives and PCR-negatives, typically being reported less by children and elderly adults (Fig.3) . Loss of taste/smell were most frequently reported in symptomatic PCR-positives in those aged ~20y, decreasing gradually with age, and were rare in symptomatic PCR-negatives, consistent with their high specificity for SARS-CoV-2. Sore throat and headache were most frequently reported in late adolescence, irrespective of SARS-CoV-2 A c c e p t e d M a n u s c r i p t 12 positivity. Cough was common and reported similarly in both symptomatic PCR-positives and PCRnegatives to ~10y. However, above 20y the proportion reporting cough in symptomatic PCRpositives was more than double that in PCR-negatives, and increased to ~60y. Similar patterns were observed for fatigue/weakness, shortness of breath, and diarrhoea. Adjusting for calendar time, age and ethnicity, women were more likely than men to report most symptoms (Fig.4) . Increased reporting in women was significantly greater in symptomatic PCRpositives than PCR-negatives for loss of smell and taste, diarrhoea and shortness of breath, and significantly smaller for headache and sore throat (all heterogeneity p<0.01). In symptomatic PCRpositives, females were significantly less likely to report fever than males, whereas in PCR-negatives there was no evidence of difference in reporting fever between males and females (heterogeneity p<0.001).

After adjusting for calendar time, age and sex, non-white ethnic groups were more likely to report fever than white ethnic groups, and less likely to report headache, nausea/vomiting and shortness of breath in both symptomatic PCR-positives and PCR-negatives (Fig.4) . In symptomatic PCR-positives, those from non-white ethnic groups were significantly less likely to report loss of taste/smell and shortness of breath than white ethnic groups, whereas in PCR-negatives there was no evidence of differences for loss of taste/smell, and much smaller differences for shortness of breath (heterogeneity p<0.01).

A c c e p t e d M a n u s c r i p t 13 13

In adjusted analyses, any symptoms were reported less frequently in those single or double vaccinated vs. unvaccinated, similarly in PCR-positives and PCR-negatives (Fig.5, heterogeneity p>0.44). In PCR-positives, ten of twelve symptoms were less frequently reported in those double vaccinated than unvaccinated (Fig.5) ; but seven of these were more frequently reported in double vaccinated than unvaccinated PCR-negatives.

At low Ct values (≤20; high viral load), the most commonly reported symptoms were cough, fatigue/weakness, headache and muscle ache/myalgia, occurring in >50% of symptomatic PCRpositives ( Fig.6 ; adjusted for viral variant in Fig.S4 ). Above Ct>27.5 (low viral load), all symptoms declined in prevalence with a trajectory that tracked Ct; between 20-27.5, most symptoms showed little variation. Interestingly, reported loss of taste/smell increased substantially from ~30% to ~45% between Ct 15-27.5, with smaller increases for shortness of breath. These symptoms may occur later in infection, hence the apparently inverse relationship between viral load and symptom prevalence.

Over the whole study, PPV of any symptoms for identifying PCR-positives was 9%. Among For a fixed number of 1-8 symptoms, choosing whether to maximise sensitivity or area under the receiver operating characteristic (AUROC) curve, or to minimise TPC or inflation factor, led to different optimal combinations (Table S7) . However, these frequently included one or more of the classic four symptoms. Sensitivity was generally higher for combinations including fatigue/weakness and/or headache, but these resulted in higher TPC, particularly for headache. Including gastrointestinal symptoms had the lowest TPC, but also lowest sensitivity. In those double vaccinated, sore throat had similar effects on sensitivity and TPC as headache, and in children diarrhoea had greater benefits for sensitivity (Table S7) .

Balancing different performance metrics, adding fatigue/weakness to the classic four symptoms improved sensitivity from 74% to 81%, while dropping AUROC by <0.01 (0.734 to 0.727) (Fig.7) .

However, TPC increased from 4.6 to 5.3, and 1.3 times more people would need testing. This combination generally performed well across subgroups (Table S8) . Adding other symptoms to the classic four symptoms generally led to lower AUROCs, and at best similar sensitivity ( Table S8, Fig.7) , excepting children/adolescents in whom adding headache achieved highest sensitivities when considering adding only one extra symptom, and also highest AUROC for those aged under 10y ( Fig.S5-S9) . In a confirmatory logistic regression, associations with positivity were strongest for reporting loss of smell or taste, and then fever, fatigue weakness, cough, muscle ache myalgia, headache and shortness of breath (Fig.S10) .

A c c e p t e d M a n u s c r i p t 15 15

Considering symptoms over time in PCR-positive episodes with 2 visits within 35 days (Table S9) , the most common symptoms presenting after the index positive were fatigue/weakness (8%), headache (7%), cough (6%), loss of taste (6%), loss of smell (5%) or muscle ache/myalgia (5%) ( Table   S10) . For most symptoms, Ct values were highest in those never reporting the symptom, lowest in those reporting it initially and subsequently, and intermediate where symptoms were reported at either the initial or subsequent visits only (Fig.S11) . The main contrast was loss of taste and loss of smell, where Ct values were lowest in those reporting loss of taste or smell at subsequent visits only (p<0.0001).

Here, we investigated the performance of symptom-based approaches to PCR testing for SARS-CoV-2 using a large community-based UK survey. Notably, reporting of any symptoms in SARS-CoV-2 infections varied substantially over calendar time (40-70%), reflecting changing dominance of specific variants (Alpha, Delta), positivity rates (higher viral burden symptomatic infections being identified more frequently when incidence is increasing [5] ), and background incidental changes (e.g. public awareness of SARS-CoV-2-associated symptoms, seasonal pathogens, schools re-opening).

Symptom reporting in PCR-positives vs PCR-negatives varied by age, sex, ethnicity and vaccination status. This variability highlights the importance of considering local context when developing symptom-based screening strategies. Broadly, in our setting, of the 12 symptoms evaluated, the four classic symptoms gave close to optimal symptom-based screening performance given limited testing capacity. Where additional testing capacity is available, adding fatigue/weakness improved sensitivity most (+7%) whilst inflating TPC by only 15%. Lateral flow antigen tests (LTFs) add a further A c c e p t e d M a n u s c r i p t 16 16 dimension to testing strategies, not evaluated here. However, LFT sensitivity for detecting symptomatic cases is lower than PCR [14] , reflected in the current guidance for LFT use for asymptomatic cases only.

Whilst the CDC approach of using a broad range of symptoms to prompt testing maximises sensitivity of case detection, it has substantially higher TPC (8.7 vs 4.6 for classic symptoms) and total tests (2.3-fold) with associated costs and capacity requirements. The UK approach, focussing on four classic symptoms, has lower sensitivity (74% vs 90%), but higher accuracy to detect symptomatic infection overall (AUROC 0.734 vs 0.593). Increased sensitivity from adding symptoms to the four classic symptoms typically reduced overall accuracy and/or increased TPC and tests needed, highlighting the importance of evaluating several test metrics. Advantages from including additional symptoms were limited, but those that best improved sensitivity across multiple subgroups included fatigue/weakness or muscle ache/myalgia, or, in children/adolescents, headache. The REACT study [7] evaluating symptom constellations during the Alpha wave (December-2020/January-2021) suggested adding headache, muscle aches, chills and appetite loss to the classic symptoms. Our survey did not specifically elicit chills or appetite loss; however, we found headache had poorer specificity, being commonly reported in PCR-negatives, particularly adults, leading to substantially increased TPC. To optimise sensitivity, REACT proposed different symptom combinations for adults and children, requiring careful public health messaging. ZOE [8] suggested an algorithm also including working in healthcare; whilst this could theoretically be programmed into an online test system, such complexity risks gaming the system if individuals cannot otherwise access tests. The main limitation is that the survey collected only 12 specific symptoms, plus one generic question, to minimise participant burden. We therefore could not evaluate some symptoms more recently proposed for inclusion, such as coryza [15, 16] . Parents/carers reported symptoms for children; symptom reporting may be affected by other cultural differences we could not adjust for, and by public awareness (e.g. increased reporting of loss of taste/smell once this became recognised). Power was limited within some subgroups, e.g. children and specific non-white ethnic groups. The survey does not include those in care homes or hospitalised with severe disease who may have different symptom profiles. Whilst the survey randomly and continuously selects households from address lists, and survey participants broadly reflect the wider population (Tables S3-S6), they are slightly older and more likely to report white ethnicity. Testing was predominantly monthly; although individuals were followed longitudinally, we had limited resolution to assess the short-term evolution of symptoms during infection. Virus Watch showed that fever and loss of taste/smell occurred later in the disease course[9], with similar findings for fever in ZOE[17].

However, they were all still chosen in the top performing symptoms for screening, suggesting this may have limited impact.

The main study strengths are its size and population representativeness, particularly capturing mild infections in the community. We took a stringent approach to defining our 'PCR-negative' comparator to limit possible contamination from undetected infections/ongoing COVID-19. We report over periods that include different dominant viral variants. Rather than optimising individual criteria, we compared predictive performance taking into account trade-offs between overall accuracy, sensitivity and TPC over different background prevalences, reflecting practical concerns regarding testing capacity.

A c c e p t e d M a n u s c r i p t 18 18 Overall, given performance trade-offs, we did not find any major shift away from the importance of the classic four symptoms in PCR-positives, despite changes associated with the emergence of Delta and vaccine roll-out. Given their concurrent changes in PCR-negatives, recent reports of associations with sore throat may reflect background increases in other respiratory infections/hayfever, potentially even with SARS-CoV-2 isolated incidentally given that one-third of cases are plausibly asymptomatic [4] . Currently, we therefore have limited evidence for expanding the case definition beyond the classic four symptoms where universal PCR testing is not practical/affordable. However, this requires ongoing monitoring as other respiratory viruses increasingly circulate following lifting of restrictions with vaccine roll-out [18] [19] [20] [21] , potentially altering the specificity of symptoms in determining SARS-CoV-2 vs other community-acquired infections.

M a n u s c r i p t Note: models adjusted for calendar date (Fig.2) , age (Fig.3) , sex (Fig.4) and ethnicity (Fig.5) . Where 95% CI cross 1, there is no evidence that vaccination status affects the odds of reporting that symptom given evidence of symptoms in PCR-positives/PCR-negatives. Where there is evidence of heterogeneity, there is a different effect of vaccination status on reporting the symptom in PCRpositives vs PCR-negatives. 

Ct threshold values, a proxy for viral load in community SARS-CoV-2 cases, demonstrate wide variation across populations and over time

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