Characterising post-COVID syndrome more than 6 months after acute infection in adults; prospective longitudinal cohort study, England

  1. Zahin Amin-Chowdhury
  2. Ross J Harris
  3. Felicity Aiano
  4. Maria Zavala
  5. Marta Bertran
  6. Ray Borrow
  7. Ezra Linley
  8. Shazaad Ahmad
  9. Ben Parker
  10. Alex Horsley
  11. Bassam Hallis
  12. Jessica Flood
  13. Kevin E Brown
  14. Gayatri Amirthalingam
  15. Mary E Ramsay
  16. Nick Andrews
  17. Shamez N Ladhani

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Abstract

Background

Most individuals with COVID-19 will recover without sequelae, but some will develop long- term multi-system impairments. The definition, duration, prevalence and symptoms associated with long COVID, however, have not been established.

Methods

Public Health England (PHE) initiated longitudinal surveillance of clinical and non-clinical healthcare workers for monthly blood sampling for SARS-CoV-2 antibodies in March 2020. Eight months after enrolment, participants completed an online questionnaire including 72 symptoms in the preceding month. Symptomatic mild-to-moderate cases with confirmed COVID-19 were compared with asymptomatic, seronegative controls. Multivariable logistic regression was used to identify independent symptoms associated with long COVID.

Results

All 2,147 participants were contacted and 1,671 (77.8%) completed the questionnaire, including 140 (8.4%) cases and 1,160 controls. At a median of 7.5 (IQR 7.1-7.8) months after infection, 20 cases (14.3%) had ongoing (4/140, 2.9%) or episodic (16/140, 11.4%) symptoms. We identified three clusters of symptoms associated with long COVID, those affecting the sensory (ageusia, anosmia, loss of appetite and blurred vision), neurological (forgetfulness, short-term memory loss and confusion/brain fog) and cardiorespiratory (chest tightness/pain, unusual fatigue, breathlessness after minimal exertion/at rest, palpitations) systems. The sensory cluster had the highest association with being a case (aOR 5.25, 95% CI 3.45-8.01). Dermatological, gynaecological, gastrointestinal or mental health symptoms were not significantly different between cases and controls.

Conclusions

Most persistent symptoms reported following mild COVID-19 were equally common in cases and controls. While all three clusters identified had a strong association with previous COVID-19 infection, the sensory cluster had the highest specificity and strength of association.

Key points

Compared to controls, we identified three clusters of symptoms affecting the sensory, neurological and cardiorespiratory systems that were more prevalent among cases. Notably, gastrointestinal and dermatological symptoms and symptoms related to mental health were as prevalent among cases as controls.

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  1. ScreenIT

    SciScore for 10.1101/2021.03.18.21253633: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: Participants were provided with information about the study and provided written informed consent prior to enrolment.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Study design and participants: In March 2020, PHE initiated a prospective cohort study (ESCAPE) of PHE and National Health Service (NHS) healthcare workers to collect monthly blood samples for SARS-CoV-2 antibodies at multiple sites in England (PHE London, PHE Porton Down, PHE Manchester, NHS Manchester Royal Infirmary and NHS Wythenshawe Hospital).
    SARS-CoV-2
    suggested: None
    Software and Algorithms
    SentencesResources
    12 In brief, blood samples were tested using five different assays for Nucleoprotein (Roche N and Abbott) and for Spike (EUROIMMUN, Roche S, and an in-house assay named RBD) antibodies.
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    Data management and statistical analyses: Data were managed using Microsoft Access (Microsoft Corporation, Redmond, Washington) and analysed using Stata 15.1 (StataCorp LLC, College Station, Texas).
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    A major limitation with all such studies, as highlighted by our study, is the lack of a control group to allow attribution of specific symptoms to long COVID. This is exemplified by reported long COVID symptoms such as headache (44%) and hair loss (25%) which were among the top five prevailing symptoms in a systematic review of long COVID.5 In our cohort, hair loss was much rarer and not significantly different among cases and controls (9.3% vs 7.4%, respectively), while headache was comparably common (46% cases vs.47 % controls). One US study surveyed 357 COVID-19 cases (9 of whom were hospitalised, 2.5%), 5,497 SARS-CoV-2 negative controls, and 19,095 non-tested individuals and found that 42.3% of cases had at least one persisting symptom at 30 days compared to 13.3% and 8.6%, respectively, with 14.8% still have at least one symptom after 90 days.9 This survey found a higher risk of persistent symptoms in those who were initially more ill. The most significant persisting symptoms in those with COVID-19 were anosmia, ageusia, difficulty concentrating, dyspnoea, memory loss, confusion, chest pain, and pain with deep breaths.9 The findings are similar to our cohort. Interestingly, while 14% of those with COVID-19 in our cohort reported on-going symptoms after 6 months, most of their symptoms were non-specific and those with more typical persisting symptoms associated COVID-19 such as anosmia or ageusia did not consider them persistent symptoms associated with their initial COV...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.03.18.21253633 on medRxiv