What are the long-term symptoms and complications of COVID-19: a protocol for a living systematic review [version 1; peer review: 1 approved with reservations, 1 not approved]

Although the majority of patients with COVID-19 will experience mild to moderate symptoms and will recover fully, there is now increasing evidence that a significant proportion will experience persistent symptoms for weeks or months after the acute phase of the illness. These symptoms include, among others, fatigue, problems in breathing, lack of smell and taste, headaches, and also depression and anxiety. It has also become clear that the virus has lasting effects not only on the respiratory system but also on other parts of the body, including the heart, liver, and the nervous system. In this paper we present a protocol for a living systematic review that aims to synthesize the evidence on the prevalence and duration of symptoms and clinical features of post-acute COVID-19 and its longterm complications. The living systematic review will be updated regularly, initially monthly with update cycles under continuous review as the pace of new evidence generated develops through the pandemic. We will include studies that follow up with COVID-19 patients who have experienced persistent mild, moderate or severe symptoms, with no restrictions regarding country, setting, or language. We will use descriptive statistics to analyse the data and our findings will be presented as infographics to facilitate transcription to lay audiences. Ultimately, we aim to support the work of policy makers, Open Peer Review


Background
More than six months into the pandemic, our knowledge around COVID-19 continues to develop rapidly. The range of documented COVID-19 infections vary from asymptomatic to severe, but the vast majority of patients experience mild to moderate symptoms and do not require hospitalisation 1 . We have previously conducted a rapid review of the literature to identify which symptoms and signs might differentiate mild and moderate from severe COVID-19 2 . Since then, and as more data are being gathered, there is increasing evidence of a "long-tail" of COVID-19 illness, but limited information about the range and duration of symptoms experienced 3 or longer term health complications. A community app developed at King's College London, which tracks self-reported symptoms, has shown that about one in ten will be sick for three weeks or more (https://covid.joinzoe.com/post/covid-long-term). Some individuals with COVID-19 have reported "fatigue, headaches and tingling nerves" that lasted months after symptom onset 4 . A recent longitudinal cohort of 143 patients followed after hospitalisation from COVID-19 in Italy reported that 87% had at least one ongoing symptom, most (55%) reporting three or more, at 60 day follow up. Fatigue (53%), dyspnoea (43%), joint pain (27%) and chest pain (22%) were the most common ongoing symptoms 5 , but there is a variety of other symptoms and complications that have been reported including neurocognitive difficulties, muscle pains and weakness, gastrointestinal upset, rashes, metabolic disruption, thromboembolic conditions and mental health conditions 6 . A prolonged course of illness has also been reported among people with mild COVID-19 who did not require hospitalisation 3,7,8 .
The evidence to date remains fragmented as to the onset of symptoms and clinical features, how long symptoms may last, how this relates to the severity of the initial illness, and further lasting impacts to health. A better understanding of patients' projected recovery from COVID-19 is helpful to patients, healthcare professionals, policymakers and commissioners. The clinical management of persisting symptoms of COVID-19 has started to be addressed in the clinical literature 6 and NHS England has issued guidance for the multisystem needs of patients recovering from COVID-19 9 . Our findings could help identify people requiring additional rehabilitation services and, where necessary, specialist referral to establish a secondary cause of their symptoms. Our findings will also be relevant to organisations such as NHS England, which have recently launched an online COVID-19 rehab service supporting patients suffering long-term effects of the disease (https://www.yourcovidrecovery.nhs.uk/) or the British Society of Immunologists, which recently released a briefing note recommending research into the long-term immunological health consequences of COVID-19 10 .
The aim of this review is to synthesize the evidence on the prevalence and duration of symptoms and clinical features of post-acute COVID-19 and its long-term complications. This will inform clinical and public health management, prevention and rehabilitation policies.

Methods
To address the aim of this study we will conduct a living systematic review (LSR). LSRs are used in areas where research evidence is emerging rapidly, current evidence is uncertain, and new research may influence policy or practice decisions 11 . These are all features of COVID-19 research, where much about the long-term effects of the disease are still unknown and policy makers are calling for more evidence. The review will be initially updated monthly, with update cycles under continuous review as the pace of new evidence generated develops through the pandemic. We aim to continue to update the review for up to two years. Our study methodology has been developed and strengthened through consultation with Long Covid Support (a patient support network).

Inclusion/exclusion criteria
We will include studies that meet the follow criteria: Search strategy A search of the following databases will be conducted: Pubmed and CINAHL through the EBSCO database host for general health peer-reviewed articles and Global Health for global peer-reviewed articles through the Ovid database host. In addition, we will search Cochrane for relevant systematic reviews and Google Scholar for grey literature including pre-prints. We will also look at the WHO Global Research Database on COVID-19 and LitCOVID as two databases that bring together evidence on COVID-19 from a worldwide dataset. Finally, we will contact experts in the field and use social media to identify relevant studies.
Data will be managed using the review software Rayyan 12 .

Key search terms
We will search using controlled subject headings and keywords of the following concepts: S3. "long-term Covid" OR long-term N2 consequence* OR "long-term impact" OR "long-term effect" OR "postacute" OR long-tail OR persist* OR "chronic-COVID" OR "long-COVID" OR post-discharge OR postdischarge OR "prolonged symptom" OR "long-haul" .ab 25,598 S4. S1 AND S2 AND S3 309 Screening Initial screening of titles and abstracts as well as full text screening against the inclusion criteria will be done by two reviewers. Disagreements for inclusion will be resolved by consensus. Where disagreements cannot be resolved, a third researcher will review the papers to make the final decision.

Critical appraisal checklist
We will be using the Hoy et al. checklist 13 to critically appraise the studies included in the review.

Data extraction
The following information will be extracted from each study based on the extraction form used for our initial review 2 : study aim, country of study, setting, method, study design and population size and characteristics, types and frequency of symptoms reported, onset and duration of symptoms. Data extraction will be performed by one reviewer and checked by a second reviewer. Disagreements will be resolved through discussion and consensus.

Data analysis
We will use descriptive statistics to summarise the types of symptoms, their frequency and duration. We will perform subgroup analysis on the basis of age, sex, comorbidities and severity of the disease. The data will be presented as infographics to facilitate transcription to lay audiences.

Protocol registration
This protocol report is structured according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement guidelines 14 , was registered with PROSPERO (CRD42020211131, 25 September 2020). The protocol will be updated as we progress with the living review as and if needed. CS is the guarantor for this study.

Data availability
Underlying data No underlying data are associated with this article. guidelines of performing systematic reviews and meta-analyses. Moreover, the protocol was registered in PROSPERO. Critical appraisal was proposed according to Hoy et al. 2012, and authors are expected to ensure that relevant criteria of risk of bias can be assessed by this tool.

Reporting guidelines
In summary, while the indexing of the paper is endorsed, several minor queries still need to be addressed, as detailed below.

Search strategy:
Authors claim that their search will not be restricted by country and language. However, it is unrealistic to identify and analyse written materials in more than 3 or 4 main languages, and these languages (English plus…) should be explicitly mentioned in the study protocol.

Data extraction:
I wonder why no data on treatment (therapy of COVID-19 symptoms) are included in the data extraction matrix. This information is crucial if aspects such as symptom severity and duration are being evaluated.

Data analysis:
This section is not well elaborated. Basic descriptive statistics only are mentioned. However, systematized data from respective publications will probably allow additional, more informative ways of synthesizing the data.

Is the rationale for, and objectives of, the study clearly described? Yes
Is the study design appropriate for the research question? Yes