A reliable and valid measure of COVID-19 patient-reported symptoms in outpatients: the Symptoms Evolution of COVID-19 (SE-C19) instrument

  1. Diana Rofail
  2. Pip Griffiths
  3. Giulio Flore
  4. Mohamed Hussein
  5. Sumathi Sivapalasingam
  6. Anna J. Podolanczuk
  7. Ana Maria Rodriguez
  8. Vera Mastey
  9. Chad Gwaltney

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Abstract

Background

There is no valid and reliable patient self-reported measure assessing symptomology among outpatients with COVID-19. The Symptoms Evolution of COVID-19 (SE-C19) is a self-administered new instrument that includes 23 symptoms, each rated for severity at their worst moment within the last 24 hours. We studied the psychometric properties of SE-C19.

Methods

Reliability, validity, and sensitivity to change of the SE-C19 were assessed in 657 outpatients with confirmed COVID-19 enrolled in NCT04425629 . SE-C19 and Patient Global Impression of Severity (PGIS) were administered daily from baseline (predose at Day 1) to end of study (Day 29).

Findings

Most patients (70·0%) were aged ≤50 years and white (85·5%). At baseline, patients reported an average (SD) of 6·6 (3·9) symptoms (ie, rated as at least Mild) with 3·8 (3·3) of these symptoms being rated as Moderate or Severe . By Day 29, most symptoms had resolved; 74·4% of patients reported no symptoms and on average, only 0·6 (SD 1·5) symptoms were reported as at least Mild .

Stable patients according to the PGIS showed scores with intraclass correlation values indicating moderate-to-good test-retest reliability (ie, 0·50-0·90). At baseline, 20 item scores (87%) varied significantly across PGIS defined groups supporting the validity of SE-C19.

A symptom-resolution endpoint was defined after excluding the item “Sneezing”, due to its low ability to discriminate severity levels, and “Confusion”, “Rash”, and “Vomiting”, due to their low prevalence in this population. Symptoms resolution required complete absence of all remaining items, except “Cough”, “Fatigue”, and “Headache”, which could be Mild or Moderate in severity.

Interpretation

We identified 19 items that are valid and reliable to measure disease-related symptoms in COVID-19 outpatients and propose a definition of symptom resolution that could be used in future clinical trials and potentially, also in clinical practice.

Funding

This research was funded by Regeneron Pharmaceuticals, Inc.

Research in context

Evidence before this study

The majority of COVID-19-infected patients (>80%) have mild-to-moderate symptoms and are managed at an outpatient setting. Although clinical research has primarily focused on prevention of the disease and the treatment of hospitalised patients, close monitoring of the COVID-19 symptoms and their severity in outpatients is equally important and needed to prevent community transmission. Patient-reported outcome (PRO) instruments are a key method to assess COVID-19 related symptoms and associated burden as these symptoms are best known by the patient and are best measured from the patient perspective. However, a valid and reliable instrument to assess symptom severity and progression among outpatients with COVID-19 is not yet available. This study focuses on the psychometric properties (reliability, validity, and sensitivity to change) of a new recently developed self-administered PRO symptom measure (SE-C19) for COVID-19-positive outpatients.

Added value of this study

This is the first study to systematically examine the psychometric properties of a PRO symptom measure designed for COVID-19 outpatients and it provides a method for identifying symptom resolution among outpatients, which may be useful in clinical research and clinical practice contexts. The SE-C19 instrument is a self-administered questionnaire that assesses the severity of 23 COVID-19-related symptoms. The recall period is 24 hours and the response options include None, Mild, Moderate and Severe . The analyses reported here demonstrate that the SE-C19 is a valid and reliable measure to capture daily COVID-19 symptom severity from the outpatient’s perspective. These psychometric analyses also provide empirical evidence for a method to determine symptoms resolution based on the score of 19 of the SE-19 items; this may be useful not only in clinical trials but also in real-world studies and clinical practice. The 4 items not included in the symptoms resolution endpoint may be useful to clinicians to monitor severe disease.

The SE-C19 instrument is relevant for the clinical management of outpatients, as it measures a large number of symptoms that are relevant in the outpatient setting and reflect the heterogeneity of symptom experience, and it is sensitive to the longitudinal changes in the severity of these symptoms.

Implications of all the available evidence

The SE-C19 can be used to monitor COVID-19-related symptoms over time in outpatients. The definition of symptoms resolution established here can be used to inform clinical trial endpoints and may also be useful in clinical practice to aid discussions between healthcare professionals and patients, and inform treatment decisions. Symptoms resolution is based on 19 of the 23 items included in the SE-C19 instrument.

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  1. ScreenIT

    SciScore for 10.1101/2021.12.16.21267708: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    RandomizationStudy population: Psychometric properties of SE-C19 were studied in symptomatic patients recruited in the NCT04425629 (COV-2067) trial, an ongoing, adaptive, phase 1/2/3, randomised, double-blinded, placebo-controlled study assessing the efficacy and safety of the combination of the casirivimab with imdevimab monoclonal antibodies, in adult outpatients with COVID-19.16 Patients could be symptomatic or asymptomatic at baseline but all patients needed a positive RT-qPCR in nasopharyngeal swab samples at randomisation.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04425629RecruitingSafety, Tolerability, and Efficacy of Anti-Spike (S) SARS-Co…

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2021.12.16.21267708v1 on medRxiv