OMICRON-ASSOCIATED CHANGES IN SARS-COV-2 SYMPTOMS IN THE UNITED KINGDOM

In this study of predominantly mild community-based infection, Omicron was associated with fewer lower and more upper respiratory tract symptoms. Increases in sore throat (also common in symptomatic PCR-negative participants), and the marked reduction in the previously highest specificity symptoms, namely loss of taste/smell, mean Omicron is harder to detect with symptom-based testing algorithms.


A B S T R A C T
In this study of predominantly mild community-based infection, Omicron was associated with fewer lower and more upper respiratory tract symptoms. Increases in sore throat (also common in symptomatic PCR-negative participants), and the marked reduction in the previously highest specificity symptoms, namely loss of taste/smell, mean Omicron is harder to detect with symptom-based testing algorithms.
. CC-BY 4.0 International license It is made available under a perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 4 As the highly-transmissible SARS-CoV-2 Omicron variant increases in incidence, coincident with other winter respiratory viruses circulating in the Northern hemisphere, changes in symptomatology may influence clinical and testing policy. Experimental and clinical data suggest Omicron has less impact on the lower respiratory tract, leading to less severe disease [1], and potentially also affecting other symptoms.
Using the UK Covid-19 Infection Survey, a nationally representative longitudinal household survey [2], we compared symptoms reported in SARS-CoV-2 PCR-positive infection episodes and PCR-negative visits in December-2021, when Omicron emerged and rapidly became dominant UK-wide [3] (Fig.1A), with October-2020 to November-2021 (described previously to August-2021[4]). Ethical approval was provided by the South Central Berkshire B Research Ethics Committee (20/SC/0195).
As Omicron started to dominate, the percentage of PCR-positives reporting symptoms, and mean number of symptoms reported, declined slightly before rising again ( Fig.1B/ is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 in PCR-negatives. Amongst symptomatic PCR-positives, there was a marked decline in reported loss of taste/smell, from 44%/44% on 1-December-2021 to 13%/11% on 31-December-2021 (Fig.1D); loss of taste/smell remained uncommon in symptomatic PCRnegatives throughout (Fig.1F). There were concurrent smaller, but significant declines in symptomatic PCR-positives reporting cough, fever, fatigue/weakness, headache, myalgia and shortness of breath with Omicron ( Fig.1D/E), with little change in symptomatic PCRnegatives ( Fig.1F/G). Trends were similar for most other symptoms (Fig.S1). The key exception was sore throat, increasing from 45% to 59% in symptomatic PCR-positives during December-2021, but also increasing from 41% to 45% in symptomatic PCR-negatives. There was a concurrent trend towards increasing reports of runny nose in symptomatic PCRpositives (Fig.S1). Differential symptom reporting between variants, particularly fewer cases with loss of taste/smell and more with sore throat, was unaffected by vaccination status (Fig.S2).
Overall, in this study of predominantly mild community-based infection, Omicron was associated with fewer lower and more upper respiratory tract symptoms. Increases in sore throat (also common in symptomatic PCR-negative participants), and the marked reduction in the previously highest specificity symptoms, namely loss of taste/smell, mean Omicron is harder to detect with symptom-based testing algorithms. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ; https://doi.org/10.1101/2022.01.18.22269082 doi: medRxiv preprint 6 . CC-BY 4.0 International license It is made available under a perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ; https://doi.org/10.1101/2022.01.18.22269082 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ; https://doi.org/10.1101/2022.01.18.22269082 doi: medRxiv preprint
Individuals were asked about demographics, symptoms, contacts and relevant behaviours (https://www.ndm.ox.ac.uk/covid-19/covid-19-infection-survey/case-record-forms). To reduce transmission risks, participants ≥12 years self-collected nose and throat swabs following study worker instructions. Parents/carers took swabs from children <12 years. At the first visit, participants were asked for (optional) consent for follow-up visits every week for the next month, then monthly from enrolment.
Swabs were analysed at the UK's national Lighthouse Laboratories at Milton Keynes and Glasgow using identical methodology. RT-PCR for three SARS-CoV-2 genes (N protein, S protein and ORF1ab) used the Thermo Fisher TaqPath RT-PCR COVID-19 Kit, and were analysed using UgenTec FastFinder 3.300.5, with an assay-specific algorithm and decision mechanism that allows conversion of amplification assay raw data from the ABI 7500 Fast into test results with minimal manual intervention. Samples are called positive if at least a single N-gene and/or ORF1ab are detected (although S-gene cycle threshold (Ct) values are determined, S-gene detection alone is not considered sufficient to call a sample positive).
The presence of 12 specific symptoms in the previous seven days was elicited at each visit from the start of the survey (cough, fever, myalgia, fatigue, sore throat, shortness of breath, headache, nausea, abdominal pain, diarrhoea, loss of taste, loss of smell), as was whether participants thought they had (unspecified) symptoms compatible with COVID-19. Any positive response to any of these symptom questions defined the case as symptomatic. Four additional symptoms (runny nose, trouble sleeping, loss of appetite, wheezing) were added in 29-September-2021; as these were not consistently elicited throughout the survey they are reported separately and not used to define a case as symptomatic.
We included the first positive study test in each PCR-positive infection "episode", defining re-infections (arbitrarily) as occurring ³120 days after an index positive with a preceding negative test, or after 4 . CC-BY 4.0 International license It is made available under a perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ; https://doi.org/10.1101/2022.01.18.22269082 doi: medRxiv preprint 11 consecutive negative tests [1]. Each positive episode was characterised by viral variant as wild-type/Delta if the S-gene was ever detected (by definition, with N/ORF1ab/both), or as Alpha-compatible or Omicroncompatible if positive at least once for ORF1ab+N, otherwise "other" (N-only/ORF1ab-only) depending on calendar period (Fig.1A).

Choice of negative visits in the comparator group
As a comparator group, we initially included all visits where PCR tests were negative, and then, following a previous analysis to August 2021 [2], excluded visits where symptoms could plausibly be related to ongoing effects of COVID-19 or long COVID, where there was a high pre-test probability that the participant actually had a new COVID-19 infection that had not been detected in the survey, or where symptoms were likely driven by recent vaccination. Specifically, we excluded all negative visits: 1. From -90 days before the first S-antibody positive blood test in the study prior to vaccination, where such antibody results are likely to represent previous undetected infection (these results were available only in a random subset of the population); 2. From -35 days before the first swab positive onwards from individuals who ever tested PCR positive in the study or positive on either PCR or LFD in the linked English testing programme (to avoid ongoing long COVID symptoms, [3] and COVID-related symptoms occurring shortly before the positive test); 3. From -35 days before any self-reported positive swab test result onwards (for the same reason; reflecting the fact that individuals may have obtained tests elsewhere) 4. From a small number of individuals who reported either loss of taste or loss of smell at their first study visit and had no national testing programme result within [-21,+21] days (all before 1 July 2020), given the high specificity of this symptom for COVID-19 infection, the fact that it would have been impossible for these individuals to get an external test at the time and the potential for subsequent symptoms to represent long COVID; 5. Where participants reported self-isolating OR contact with definite positives in the preceding 28 days (since these individuals have much higher risk of SARS-CoV-2 infection which may not have been detected) and the previous and the next visit (because of higher risk of unidentified positivity, and because they may have been contact traced through the national training programme they may be more likely to report symptoms through recall bias, regardless of status); . CC-BY 4.0 International license It is made available under a perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 6. Occurring within [-7,+14 days] of either first, second or third vaccination date [4], to avoid the inclusion of common symptoms caused by vaccination in the test-negative comparator group and to reflect the possibility of small inaccuracies in reported date of vaccination for some participants.
Time windows were arbitrary but aligned with other analyses or windows for considering symptoms associated with PCR-positive episodes.

Choice of timeframe to include symptoms in the PCR-positive group
Tests are conducted in the survey independently of symptoms, and therefore infection episodes may be identified either early (pre-symptomatic) or late (post-symptomatic). Symptom questions relate to the previous 7 days, so to ensure that subsequently reported symptoms in pre-symptomatic cases were counted we included all symptoms reported at any visit (PCR-positive/PCR-negative/failed) up to 35 days after the index positive test in each infection episode, reflecting the monthly visit schedule.
is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ; https://doi.org/10.1101/2022.01.18.22269082 doi: medRxiv preprint 13 sex:Sars_COV_2_positivity + ethnicity_wo:Sars_COV_2_positivity + sex + ethnicity_wo + Sars_COV_2_positivity, family=gaussian, method = "fREML", data = data, discrete=TRUE, nthreads =12) To explore the differences between Delta and Omicron by vaccination status we restricted our PCRpositives to those occurring after 1-December 2021 and classified S-gene positives and S-gene negatives by their vaccination status at the time of the index positive test: before first vaccination (unvaccinated), from 21 days after first vaccination to 13 days inclusive after second vaccination (first vaccine), from 14 days after second vaccination to 13 days inclusive after third vaccination (second vaccine), more than 14 days after the third vaccination (third vaccine).
. CC-BY 4.0 International license It is made available under a perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022  is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

Supplementary Figures
The copyright holder for this this version posted January 18, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022  is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 Declarations Contributors: This specific analysis was designed by ASW, K-DV, KBP, PCM, NS, DWE, TH, DC, TEAP. K-DV conducted the statistical analysis of the survey data. K-DV, NS, PCM, ASW drafted the manuscript. All authors contributed to interpretation of the study results, and revised and approved the manuscript for intellectual content. K-DV is the guarantor and accepts full responsibility for the work and conduct of the study, had access to the data, and controlled the decision to publish. The corresponding author (K-DV) attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. or PHE. The funder/sponsor did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. All authors had full access to all data analysis outputs (reports and tables) and take responsibility for their integrity and accuracy. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 18, 2022. ; https://doi.org/10. 1101/2022

Transparency:
The lead authors affirm that the manuscript is an honest, accurate, and transparent account of the study design being reported, no important aspects of the study have been omitted, and any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.
Dissemination to participants and related patient and public communities: Results of individual tests were communicated to the participants. Overall study results were disseminated through the preprint of the study. Findings were disseminated in lay language in the national and local press.