A research definition for Long COVID

Abstract

 

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Background

Long COVID is characterised by a wide range of post-acute and long-term symptoms which are difficult to categorise in a single definition. Clinical definitions, such as the consensus definition developed by the WHO, are broad and inclusive but not suitable for research purposes:

Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.1

Particularly challenging for research purposes are the (highlighted items): ambiguity around confirmation of, and timeframe from, initial infection; plus the need to systematically exclude alternative explanatory medical and psychiatric diagnoses. The ambiguity regarding the functional impact of symptoms which allows inclusion of illness manifestations of minor significance. Further, the allowance for a complete gap between the initial infection and symptom onset are also problematic when considering the premise of truly COVID-induced illness. The APPRISE Long COVID research definition is therefore more restrictive to enable a better characterised and less ambiguous cohort and to facilitate analysis. The implementation of this research case definition is undertaken with validated, public-domain self-report questionnaires and protocolised further assessments which have been outlined.

Research definition of Long COVID

This is a three-part definition that can be used to characterise both new onset and previously identified cases of Long COVID.

  1. Confirmation of acute infection:

Designation of acute COVID-19 infection at onset of symptoms, either as:

a. Confirmed by molecular or antigen detection at time of acute infection, or serological confirmation (anti-Nucleocapsid IgG seroconversion between acute and convalescent samples)

OR

b. Probable acute COVID-19 infection based on an influenza-like illness (ILI) within a high risk, epidemiological context (e.g., a family cluster with at least one confirmed acute COVID-19 case)

Primary case designation

  1. Application of a modified WHO Long COVID research case definition at 12 weeks post infection:

a. New onset of ongoing symptoms – including at least one of fatigue, shortness of breath, cognitive disturbance, and sleep disturbance – which substantially impact on everyday functioning.

b. No symptom-free interval from acute infection.

c. Additional symptoms such as myalgia, disturbed taste and smell, and others may co-occur.

d. Symptoms may fluctuate over time.

  1. Rule out other known causes of the symptoms by clinical evaluation and investigation

a. The clinical evaluation should include a thorough history and physical examination, as well as a mental status examination;

b. A minimum set of laboratory screening tests should be completed (as stipulated for the diagnosis of chronic fatigue syndrome2) including:

    • full blood count with leucocyte differential;
    • erythrocyte sedimentation rate or C-reactive protein;
    • serum levels of alanine aminotransferase, total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose;
    • blood urea nitrogen, electrolytes, and creatinine
    • thyroid-stimulating hormone;
    • urinalysis;

c. Additional investigations could also be undertaken if needed to reliably identify alternative medical explanations for specific symptoms. Examples include:

    • Lung function tests including spirometry when shortness of breath is reported; or exercise oximetry and measurement of the diffusion capacity for carbon monoxide (DLCO) to identify suspected interstitial lung injury;
    • CT pulmonary angiography (CTPA) to consider pulmonary emboli;
    • ECG and echocardiography when a cardiac cause is suspected.

Secondary case designations

Syndromal designation of one or more of chronic fatigue syndrome (CFS), fibromyalgia (FM), or postural orthostatic tachycardia syndrome (POTS) may be made according to the published diagnostic criteria with the following modifications:

a. In subjects with confirmed or probable acute COVID-19 infection, and who met the modified WHO case definition for Long COVID (see above), and who remain unwell at 24 weeks post-infection an additional secondary case designation may be made, if

b. The symptom complex continues to be associated with disability – that is, it results in a substantial reduction in previous levels of occupational, educational, social, or personal activities (as specified in the CFS case definition, but added to the FM and POTS definitions);

c. The symptom complex must have been present without symptom-free interval from the time of the acute COVID-19 infection;

d. The symptom complex must not have been present prior to the acute COVID-19 infection.

 Instrumentation

A. Questionnaires (validated for each symptom domain with ‘clinically-significant’ thresholds):

    • Somatic and Psychological Health Report (SPHERE)3 – SOMA (fatigue) & PSYCH (mood disturbance) subscales4, 5
    • Modified MRC Dyspnoea scale6 – shortness of breath
    • Patient’s Assessment of Own Functioning (PAOFI )7 – cognitive disturbance
    • Pittsburgh Sleep Quality Index8 – sleep disturbance
    • WHODAS 129 – assessment of disability
    • McGill Pain questionnaire – short form10 – musculo-skeletal pain
    • Kessler Psychological Distress Scale -10 (K10)11 – psychological distress reflecting anxiety and depression
    • COMPASS 3112 – autonomic disturbance

B. Interview – Structured Clinical Interview for Neurasthenia (SCIN) 13

C. Physical examination and protocolised investigations (as previously listed)

References

  1. World Health Organisation. A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1
  2. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. Dec 15 1994;121(12):953-9. doi:10.7326/0003-4819-121-12-199412150-00009
  3. Hickie IB, Davenport TA, Hadzi-Pavlovic D, et al. Development of a simple screening tool for common mental disorders in general practice. Med J Aust. Jul 16 2001;175(S1):S10-7. doi:10.5694/j.1326-5377.2001.tb143784.x
  4. Hickie I, Koschera A, Hadzi-Pavlovic D, Bennett B, Lloyd A. The temporal stability and co-morbidity of prolonged fatigue: a longitudinal study in primary care. Psychol Med. Jul 1999;29(4):855-61. doi:10.1017/s0033291799008582
  5. Koschera A, Hickie I, Hadzi-Pavlovic D, Wilson A, Lloyd A. Prolonged fatigue, anxiety and depression: exploring relationships in a primary care sample. Aust N Z J Psychiatry. Aug 1999;33(4):545-52. doi:10.1080/j.1440-1614.1999.00593.x
  6. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. Jul 1999;54(7):581-6. doi:10.1136/thx.54.7.581
  7. Chelune G, Heaton R, Lehman R, Goldstein G. Advances in clinical neuropsychology. 1986:95-126.
  8. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. May 1989;28(2):193-213. doi:10.1016/0165-1781(89)90047-4
  9. Andrews G, Kemp A, Sunderland M, Von Korff M, Ustun TB. Normative data for the 12 item WHO Disability Assessment Schedule 2.0. Research Support, Non-U.S. Gov’t. PLoS One. Dec 17 2009;4(12):e8343. doi: 10.1371/journal.pone.0008343.
  10. Melzack R. The short-form McGill Pain Questionnaire. Pain. Aug 1987;30(2):191-197. doi:10.1016/0304-3959(87)91074-8
  11. Kessler RC, Andrews G, Colpe LJ, et al. Short screening scales to monitor population prevalences and trends in non-specific psychological distress. Psychol Med. Aug 2002;32(6):959-76. doi:10.1017/s0033291702006074
  12. Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. Dec 2012;87(12):1196-201. doi:10.1016/j.mayocp.2012.10.013
  13. Bennett BK, Goldstein D, Chen M, et al. Characterization of fatigue states in medicine and psychiatry by structured interview. Psychosom Med. Jun 2014;76(5):379-88. doi:10.1097/psy.0000000000000061

Related Research Areas

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