Long-term sequelae after SARS CoV-2 disease

Research areas: High tech medicine, Rehabilitation and occupational therapy

Duration: April 2021 – November 2021
Language: English (with German summary)

Publications: 
HTA Project Report No 135a: https://eprints.aihta.at/1321
HTA Project Report No. 135b: https://eprints.aihta.at/1342

Background: For about 14 months, the entire world has been concerned with the viral disease "severe acute respiratory syndrome coronavirus type 2" (SARS-CoV-2). The main focus to date has been on SARS-CoV-2 infection and mortality rates. The viral disease encompasses a wide spectrum of severity from asymptomatic to fatal courses of infection. However, the duration of the disease and the prevalence of long-lasting symptoms after an acute SARS-Cov-2 infection are just as heterogeneous as the course of the disease. For this reason, the focus has also shifted to possible long-term consequences of SARS-CoV-2 infections. These late effects are most often summarised under the term "long COVID". It includes all symptoms that occur after an acute SARS-CoV-2 infection and cannot be associated with any other cause. Possible long COVID symptoms include, for example, shortness of breath, high blood pressure, fatigue, olfactory and gustatory disturbances, or psychological complaints such as depression. In severe cases, organ damage, e.g., to the heart, lungs, or liver may also occur [1, 2]. To date, there is no international consensus definition at which point in time after an acute SARS-CoV-2 infection long-lasting symptoms are named long COVID. Rather, different time points are mentioned in several definitions that vary, for example, between three to 12 weeks after the onset of the acute infection [3, 6].

According to expert estimates, about 10-20% of SARS-Cov-2 patients suffer from sequelae of the acute infection [4, 5]. For Austria, this would mean that with a total of 584,000 SARS-Cov-2 cases (as of 15.04.2021) approximately 58,400 to 116,800 long COVID patients are to be expected. However, their symptoms will only become apparent with time. In addition, preliminary international data indicate that individuals of all ages and regardless of the severity of the initial SARS-CoV-2 infection may suffer sequelae [6, 7]. Thus, in addition to possible physical and psychological effects for the long COVID patients themselves and the social effects for their families, economic consequences for society as a whole need to be considered (e.g., inability to work, occupational change). It is therefore all the more important to plan treatment or other support opportunities for long COVID patients and subsequently prevent serious late effects as well as support them to return to their "normal" lives [6, 8].

The main objective of this project is to systematically and critically review the literature on the diagnosis and prevalence of conditions that may occur as long-term sequelae following an acute SARS-CoV-2 infection. In addition, the project will identify treatment and other support needs of long COVID patients. The results on the prevalence rates and possible treatment and support needs should assist preparations and adjustments in the long COVID care planning including the health care sector (e.g. rehabilitation), as well as social-legal aspects (e.g. insurance).

An effectiveness and safety analysis of the different treatment or rehabilitation options for long COVID, as well as a specific care analysis of the management and treatment of patients with long COVID in Austria, is NOT the aim of the present project.

The following research questions arise from the defined project aims:

1. Which disease patterns/symptoms/abnormal clinical parameters are associated with long COVID and what are the effects on the daily activities of the patients?
2. How is long COVID diagnosed and how often do the identified long COVID disease patterns/symptoms/abnormal clinical parameters occur?
3. Are there risk factors that promote the occurrence of long COVID?
4. What are the current management and treatment recommendations and additional support options for long COVID patients?
5. Which structural changes in service organisation for long COVID have been established or being recommended in selected countries?

Methods: Derived from the outlined research questions, the present project consists of two parts. The first part refers to the diagnosis and frequency of long COVID symptoms, while the second part covers treatment and support needs, as well as structural changes in service organisation for long COVID patients. For this reason, the methods for each part are described separately below.

Part 1: Long COVID symptoms and their diagnosis and frequencies (research questions 1-3)

A systematic literature search and an extended hand search will be conducted for the systematic literature review on possible long COVID symptoms, their impact on everyday life, diagnosis and frequencies. After selecting the literature, the data will be extracted and qualitatively summarised to answer research questions 1-3. Depending on the amount, quality, and currency of the selected literature, the data will be analysed either in the form of an "Overview of Reviews" or in the form of a "Review Update". Two authors (SW & JE) will perform all steps (literature selection, data extraction, quality assessment).

Criteria for systematic search/ inclusion criteria:

Population	Adult patients with physical, neurological/cognitive, or psychiatric long COVID symptoms from 12 weeks after acute SARS-CoV-2 infection (WHO definition). Keywords: long-covid, post-covid-syndrome, long-lasting Covid19 symptoms, chronic COVID syndrome, post-acute sequelae of SARS-CoV-2 (PASC)
Intervention	-
Control	-
Outcomes	Primary outcome: diagnosis & frequencies of long COVID disease patterns/ symptoms/abnormal clinical parameters Secondary outcomes: - Impact of long COVID on daily life (e.g., inability to work) - Risk factors for long COVID
Study design	„Overview of Reviews“: systematic reviews & meta-analyses “Review Update”: systematic reviews, meta-analyses & big, recent primary studies
Publication period	Until the end of April 2021
Countries	Europe, North America, Australia
Languages	German and English

Update: Due to the identification of an advanced report from the Belgian research institute (https://kce.fgov.be/) that addresses the same research questions as in Part 1, the methodology of Part 1 has been modified: instead of a separate systematic literature review, a detailed German summary of the KCE report will be written.

Part 2: Treatment and support needs, as well as structural changes in service organisation for long COVID patients (research questions 4-5)

For the overview of treatment and other support options, as well as structural changes in service organisation for long COVID patients, a systematic literature search, as well as a targeted hand search for guidelines and reviews, will be conducted. After selecting the literature, the data will be extracted and qualitatively summarised to answer research questions 4 and 5. Additional information on structural changes in service organisation for long COVID will be obtained via an extended hand search on established or emerging health service structures in selected European countries. The same two authors (SW & JE) will perform all steps (literature selection, data extraction, guideline assessment).

Criteria for systematic search/ inclusion criteria:

Population	Adult patients with physical, neurological/cognitive or psychiatric long COVID symptoms from 12 weeks after acute SARS-CoV-2 infection (WHO definition). (see keywords of Long-Covid Part 1)
Intervention	Treatment approaches for long COVID disease patterns/symptoms/abnormal clinical parameters Other support options (e.g., social, financial, occupational) for long COVID patients Structural changes in service organisation for long COVID patients (e.g., rehabilitation centres)
Control	-
Outcomes	-
Study design	Guidelines, reviews
Publication period	Until July 2021
Countries	Europe, North America, Australia
Language	German and English

Updated time table:

Period	Tasks
Part 1: Long COVID symptoms and their diagnosis and frequencies (research questions 1-3)
April 2021	Scoping (Hand search, literature screening, background, kick-off-meeting, project protocol)
Beginning – Mid-May 2021	Systematic literature search (search, abstract screening)
Mid-May 2021	Review of the KCE report
Beginning of June 2021	Writing of a detailed German summary including involvement of the second author
Mid-June 2021	Internal review of the German summary
Mid – End of June 2021	Layout and publication of the KCE report including detailed German summary
Part 2: Treatment and support needs, as well as structural changes in service organisation for long COVID patients (research questions 4-5)
Beginning of May 2021	Systematic literature search (search, abstract screening, full-text selection)
By July 2021	Data analysis (data extraction & control, quality assessment & control)
August 2021	Extended hand search for medical care structures in selected countries
July – End of September 2021	Writing of Part 2 including involvement of the second author
End of September 2021	Internal review of Part 2
Mid-October 2021	External review of Part 2
Beginning of November 2021	Layout and publication of Part 2

References:

[1] What might long COVID mean for the nation’s health? The Health Foundation.2021. https://www.health.org.uk/news-and-comment/blogs/what-might-long-covid-mean-for-the-nations-health. Gesehen am 15/04/2021.

[2] Greenhalgh et al. ‘Long Covid’: evidence, recommendations and priority research questions. https://committees.parliament.uk/writtenevidence/12345/pdf/. Gesehen am 15/04/2021.

[3] Long COVID: Der lange Schatten von COVID-19. Deutsches Ärzteblatt. 2020. https://www.aerzteblatt.de/archiv/217002/Long-COVID-Der-lange-Schatten-von-COVID-19. Gesehen am 15/04/2021.

[4] Davis et al. (2020). Characterizing long covid in an international cohort: 7 months of symptoms and their impact. https://www.medrxiv.org/content/10.1101/2020.12.24.20248802v2. Gesehen am 15/04/2021.

[5] Kapeller et al. (2021). Long Covid: Die Krankheit nach der Krankheit. Der Standard. https://www.derstandard.at/story/2000125715604/long-covid-die-krankheit-nach-der-krankheit. Gesehen am 15/04.2021.

[6] Living with Covid19 – Second Review. NIHR. 2021. https://evidence.nihr.ac.uk/themedreview/living-with-covid19-second-review/. Gesehen am 15/04/2021.

[7] Epidemiology of long covid: a pragmatic review of the literature. KCE. 2021. https://kce.fgov.be/sites/default/files/atoms/files/2020-04HSR_LongCOVID_COVID%20Contributions_01022021.pdf. Gesehen am 15/04/2021.

[8] Rayan (2021). As the UK inches towards normality, those with long Covid must not be forgotten. The Guardian. https://amp.theguardian.com/commentisfree/2021/apr/14/long-covid-uk-impact-society. Gesehen am 15/04/2021.