Long-term Effects of COVID-19: Long COVID

Long-term Effects of COVID-19: Long COVID

Open article published on MedShr: 26th November 2020
Last updated: 26th November 2020

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Long COVID - Origins and Nomenclature

At time of publishing this article, it is reported that over 38.5 million patients have recovered from COVID-19 infection globally.[1] However, since early in the pandemic, there has been a growing awareness of the significant proportion of people affected by SARS-CoV-2 who have symptoms persisting well beyond the early (acute) phase of the infection.[2] Patients have played a central role in promoting an awareness of these symptoms.[3

This pattern of symptoms has been termed ‘post-acute COVID-19’ (or similar) in scientific literature, but increasingly is recognised by the term Long COVID. The origin and evolution of the term Long COVID - which was created by patients experiencing persistent symptoms following an illness in with keeping COVID-19 infection - has been explored in this short communication, “How and Why Patients Made Long Covid”.[3

The underlying aetiology(ies) and risk factors are not yet clearly understood, although comparisons have been drawn to sequelae in post-viral fatigue syndrome, myalgic encephalomyelitis (chronic fatigue syndrome), and patterns from other pandemics including SARS and MERS (see summary in Greenhalgh et al. 2020).[2, 4]

These uncertainties have made it challenging to clearly define the condition (or conditions) recognised by persisting signs and symptoms thought to be secondary to SARS-CoV-2 infection.[5] On 30th October 2020, the National Institute for Health and Clinical Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and the Royal College of General Practitioners (RCGP) released their guideline scope on management of the long-term effects of COVID-19 [6], and have assumed the terminology ‘post-COVID-19 syndrome’ with the following definition: 

Quote describing the NICE, SIGN, and RCGP working definition of Post-COVID-19 Syndrome

Significantly, this definition does not use ‘Long COVID’ in it’s nomenclature, a term which several authors have argued encapsulates the heterogeneity and uncertainty of this condition without limiting the reference by severity, chronicity or excluding the scope of patients affected.[3, 7, 8] However, given the increasing recognition that long-term effects from COVID-19 are not restricted to those who have been hospitalised with a severe form of the acute phase of infection [5], this definition clearly acknowledges that a positive SARS-CoV-2 test (either PCR, antigen or antibody) is not a requirement to diagnose post-COVID-19 syndrome (see figure 1).[6] Rather, it recognises a clinical diagnosis of an infection consistent with COVID-19 - which can be made retrospectively - and therefore is inclusive of patients who had to self-manage their illness at home often without access to a test.[9] It is also important to highlight a positive antibody test is not a prerequisite for diagnosis, given the variability and uncertainty in the expected levels of antibody titres following the acute phase of infection [10, 11], and the yet to be fully examined hypothesis that weaker immune responses may be a risk factor for the development of long-term COVID-19 symptoms.[2]

Figure 1 | Working definitions of Post-COVID-19 Syndrome based on guideline scope published by the National Institute for Health and Clinical Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and the Royal College of General Practitioners (RCGP) on 30th October 2020.[6]

What do we know about Long-COVID thus far?

An accurate estimate of the prevalence of persisting symptoms from COVID-19 is not yet clear. An initial estimate from the COVID Symptom Study App, published on 6th June 2020, suggested one in ten patients using the app reported symptoms persisting for greater than three weeks.[12] A recent preprint article published on medRxiv (not yet peer-reviewed) from the same team revealed 13.3% of a sub-group of participants reported symptoms associated with COVID-19 for greater than 28 days, and 2.3% for more than 12 weeks.[13] Whilst this approach is providing valuable, rapidly available epidemiological data on long-term symptoms associated with COVID-19 [14], it is important to acknowledge a selection bias may be introduced by self-reporting of symptoms. Furthermore, the rates reported in this recent article are calculated after excluding patients who were asymptomatic, did not have a clear symptom onset, or who did not continue to regularly record symptoms on the app (overall a total of 84% of the identified PCR-confirmed cohort). However, other studies have reported even higher rates of persistent symptoms in both hospitalised patients [15, 16, 17] and non-hospitalised patients [17, 18, 17, 19]. Therefore, whilst a definitive prevalence is yet to be determined, it is clear that a significant proportion of patients infected with COVID-19 are suffering with debilitating, long-term effects which warrant urgent investigation. 

Mechanisms and aetiological factors that underlie persistent symptoms from COVID-19 infection have been hypothesised but are not yet fully understood; the British Society of Immunology have created a useful rapid-review exploring some of these factors [20], and other authors are exploring hypotheses for possible mechanisms, for example the role of mast cells [21].

Significantly, the available literature from both patient-led research groups and scientific articles (both published and preprint) frequently highlight no discernible association between the severity of initial COVID-19 infection and the risk of persistent symptoms.[2, 17, 22] In a letter to the UK Health and Social Care Committee, the Long Covid Support Group emotively described, “...acquiring Coronavirus can lead to long term debilitating and distressing symptoms no matter your age, underlying health or fitness”.[9]

Data presented in two preprint articles suggest risk factors for Long COVID may include increasing age, increasing BMI, and/or being female [13], and also experiencing more symptoms earlier in the course of the infection (used as a proxy for severity in Ciruelli et al.).[13, 23]

Symptoms of Long COVID vary markedly both for individual patients at different times of their illness, and in terms of the multiple body systems affected in different patients.[5, 22] A recent review by the National Institute of Health Research (NIHR) suggested that the multi-system and fluctuating symptoms experienced by patients may actually be due to multiple and interacting syndromes, such as Post-Intensive Care syndrome, Post-Viral Fatigue syndrome and Long-Term Covid syndrome.[5]

Figure 2 highlights a non-exhaustive list of some of the symptoms, social factors, and psychological effects commonly reported in the available literature exploring the long-term impact of COVID-19 infection (including sources that are not peer-reviewed).[5, 13, 22, 24, 25, 56] This figure is not intended to limit, define or categorise the subjective experience of this condition by patients, and there are recognised limitations to the biopsychosocial model; rather the hope is this provides an accessible summary which depicts the multiple, varied, and individualised effects this condition can have on patients, and therefore emphasise the need for a holistic approach to managing this condition.

The importance of a holistic approach when considering the biological, psychological and social effects of Long COVID
Figure 2 | The multiple and varied biological, psychological, and social effects described in association with Long COVID. This figure is not intended to limit, define, or categorise the subjective experience of this condition by patients. The intention is to provide an accessible summary which depicts the multiple, varied, and individualised effects this condition can have on patients, and therefore emphasise the need for a holistic approach to managing this condition. See text for related references.

What are the research challenges and questions to address?

From the available literature, several questions and challenges have been identified which must be addressed by future research studies into the long-term effects of COVID-19:

  • Establishing a working definition of Long COVID: as NICE suggests a working definition for long-term symptoms of COVID-19 as ‘post-COVID-19 syndrome’, it will be important to analyse how useful both patients and healthcare professionals find this as a working definition, and to be open to adapting this definition as required if new evidence emerges and our understanding of this syndrome increases. Equally, it is important to acknowledge that many patients with symptoms consistent with the working definition of ‘ongoing symptomatic COVID-19’ or ‘post-COVID-19 syndrome’ have expressed concern at the potential negative influence of current severity classifications for the acute illness phase which may lead to the misconception that any infection not resulting in respiratory compromise requiring hospitalisation is a mild case.[5] Involving patients in a discussion about what could be included in a functional grading scale for severity of living with COVID-19 will be essential [3, 26], and researchers should consider how this could be integrated with scoring or risk stratification tools for the acute phase of infection.[27] Critically, a working definition which is recognised internationally would allow for easier comparisons between different research studies.[28]

  • Identifying aetiological factors and how this translates to risk of developing Long COVID: increasing our understanding of the mechanisms which underlie COVID-19 infection is essential, with particular comparison of immunological and inflammatory responses between groups of patients with, 1) varying severity in the acute phase of infection and, 2) varying length of time to recovery or resolving symptoms.[28] If patterns can be established this may highlight risk factors which support epidemiological data for predicting groups of patients who may be at increased risk of Long COVID.[13] This would also help refine the definition of Long COVID, for example by identifying if subsets of syndromes with different predominant aetiologies exist [5], which in turn will help guide research and delivery of more focussed interventions. The possible association of persistent mild organ impairment, even in low-risk individuals (research from medRxiv, not yet peer-reviewed), with persisting symptoms of COVID-19 must also be fully explored.[29] In trying to understand the mechanisms which underlie Long COVID, calls have been made by leaders in the field of functional neurology to learn from the holistic research approaches utilised in this field which have led to several advances in understanding of these conditions.[30

  • Optimising management and rehabilitation for Long COVID: in the next section, current management strategies for Long COVID, or post-COVID-19 syndrome, are addressed, and it will clearly be essential to design these services and evaluate their impact with significant input from patients with this condition.[5, 6] It will also be important to establish if there are any management strategies which, when employed in the acute phase of infection, can reduce progression to persisting COVID-19 symptoms.[28

  • Consider the social and psychological implications of living with Long COVID: Future research must now consider the potential social and economical impact for patients who were previously employed but are temporarily (and possibly long-term) unable to work in the same role they had prior to COVID-19 infection.[5] This research would help shape support services and inform government policies to support this group of patients. Occupational health research must establish how to best accommodate for fluctuating absences amongst workforces [5], and a call has been made for the NHS to help lead the way as an adaptive and accommodating environment for employees returning to work who are suffering from symptoms of Long COVID.[9] It is also important that studies evaluating the long-term effects of COVID-19 assess the mental health effects of both acute infection and chronic symptoms. [31]

Yelin et al.[28] have suggested how these research studies could be designed, emphasising the need for multidisciplinary, multicentre, international studies. Several research studies have been launched, and are summarised in the NIHR themed review.[5] These studies aim to examine a range of patient cohorts, including:

In addition, international projects such as the COVID Symptom Study App and the Patient Led Research surveys previously mentioned, are also helping shape our understanding of Long COVID, and issues highlighted by early patient-led research has been recognised recently in a meeting with the WHO.[32] However, as with all good scientific research, it is important to ensure that study results are interpreted with reference to the study population; some challenges which should be considered with the data collected in these projects include:

  • Selection bias may be introduced from having a self-selecting sample; equally a degree of recall bias may be introduced.

  • For certain methods of data collection, e.g. smartphone apps or social media groups, participation bias could be introduced by patients at the extremes of age or with decreased ability to use these methods (e.g. children or care home residents) being unable to contribute to the results; similarly some underrepresented patient groups in medical research (e.g. homeless patients) may not have access to these technologies.[5]

  • It is also important to consider if participation bias may be introduced if patients who have recovered from COVID-19 are then less likely to continue to contribute to these data collecting methods.

Indeed, results reported from these studies highlight these issues within their publications. This should not negate the validity or value of results from these studies, but rather highlight that future research must also ensure patients from groups which may be underrepresented are included in studies exploring the long-term effects of COVID-19.[3, 5] Authors have already raised this issue, for example highlighting the importance of examining the impacts of Long COVID in paediatric patients.[33, 34]

What Support is available for patients with Long COVID?

Given the fluctuating severity and multi-system effects associated with Long COVID, it is unsurprising that both patient support groups and researchers have emphasised that services created to manage the effects of this condition must have a holistic, multidisciplinary approach.[5, 35, 36]

The NHS launched the ‘Your COVID Recovery’ website hub earlier this year, and in October committed to establishing a ‘NHS England Long Covid taskforce’, which critically will also include patients with Long COVID.[37] Furthermore, multidisciplinary clinics dedicated to Long COVID are planned across the UK, where patients will be able to access support for physical, cognitive and psychological effects from their condition.[34, 37] It will be important to design services that meet the rehabilitation needs of both hospitalised and non-hospitalised patients [19, 36], and whilst specialist secondary care clinics will play a central role, the importance of integrating these services with COVID-19 support teams in primary care and the community will also be essential.[38] Sivan et al. [38] have published guidance on how such an integrated rehabilitation pathway may be structured, and figure 3 demonstrates the scale of the specialised MDT which could be required to deliver these services.[34]

The MDT that may be required to care for patients with Long COVID
Figure 3 | The scale of the specialised MDT which could be required to deliver effective Long COVID care both in the community and in specialised hospital clinics.[34, 38]

Authors have proposed using telemedicine both for screening and delivering certain management options to try and ensure patients are able to access targeted services specific to their needs in a timely manner.[39] Similarly, novel approaches described in preprint articles such as the ABCoV-tool [40] and the COVID Symptoms Study App [13] could provide unique insight into monitoring individual disease burden and therefore directing services to patients as required.

In addition to launching these specialist hospital and community services, patient-led support groups have also called for formalised funding as recognition of the important role these groups have in supporting recovery.[9] Furthermore, in recognition of the significant mental health impact that COVID-19 - both as a direct consequence of infection or as an indirect impact from the global pandemic - may have on patients, adequate funding for mental health services will be an essential component of public health strategies going forward.[31, 41, 42] As discussed above, ensuring that there is also appropriate occupational health advocacy for patients with Long COVID to enable a supportive and adaptive return to work where possible is important.[5, 9]

How can Healthcare Professionals keep up-to-date with this guidance?

Extract from guidance from RCGP for healthcare professionals caring for patients with long COVID

One striking feature of the recent NIHR report which has also been echoed by patient support groups [9, 22], is the description of patients with Long COVID feeling like their symptoms were being doubted.[5] Qualitative research examining this emphasised the perceived therapeutic value for patients in having healthcare professionals (specifically their GP in this study) simply acknowledge and believe their symptoms, even if the optimal management going forward is not immediately clear.[43] A key challenge for the healthcare profession now is ensuring that not only is guidance for the best-evidenced management of SARS-CoV-2 in the acute phase widely available, but also that accessible, evidence-based resources are available to empower healthcare professionals to provide accurate, consistent and realistic information to patients with long-term effects of COVID-19.[2, 5] Therefore, as emphasised by the NICE guideline scope [6], it will be important that the ‘lived experiences’ of patients are incorporated into developing clinical guidelines.

Follow-up guidance for individual specialities and conditions is emerging, for example respiratory follow-up for patients with COVID-19 pneumonia [44], and considerations for managing chronic pain after COVID-19 [45]. Consensus statements from rehabilitation experts have also been produced for COVID-19 rehabilitation [46], and the NIHR living review is running webinars on a range of topics related to long COVID.[5] However, it will be important that new guidelines also provide approaches for supporting recovery and rehabilitation for patients who managed their symptoms at home and therefore may not have had documented evidence of clinical infection.[36, 38]

A key role for healthcare teams managing patients with suspected Long COVID will be ensuring that symptoms are appropriately investigated to exclude other causes before being attributed solely to SARS-CoV-2 infection.[2, 5] Such approach was highlighted in the NIHR report and has been emphasised in the definitions laid out in the NICE, SIGN and RCGP scope guidance.[6]

Challenges for Managing Long COVID in Low- and Middle-Income Countries (LMICs)

At the time of writing, there was no published literature that we could identify discussing the potential challenges of caring for patients with long COVID in low- and middle-income countries (LMICs). 

Given the potential burden of Long COVID globally, and previously identified gaps in the provision of rehabilitation services to patients living with a disability in some LMICs [47], it is essential for research to address this global need to help inform policies and guide healthcare professionals. Importantly, research into the long-term effects of COVID-19 must also consider the potential challenges patients face which are unique to their region, culture or society, as the burden of the condition is influenced by each individual's unique circumstances.[5, 48]

Examples of some specific challenges that research into the effects of Long COVID in LMICs may need to consider and address include:

  • Weak primary health care services: this was identified by the WHO as one of the greatest threats to global health in 2019 [49], and this could prove a significant challenge as primary care is likely to play a central role in providing recovery and rehabilitation services for patients with Long COVID. However, where services may need to be delivered in the context of ongoing social distancing, the potential strengths in healthcare systems built on strong networks of community health workers who can help deliver long COVID therapies to patients in their own homes should not be underestimated.[50]

  • Barriers to accessing Long COVID clinics: including challenges travelling to clinics and financial barriers in paying for access to these services.[51] Barriers could also be created by inadequate infrastructure to support follow-up and screening (e.g. by telephone) to detect patients with possible long-term effects from COVID-19.

  • Role of Telemedicine: several authors have proposed utilising telemedicine solutions for providing rehabilitation services for patients with Long COVID, but this will be dependent on the patient’s ability to access and use the technology required to enable this approach. Positively, there are reports of successful use of smartphone-based telemedicine programmes for delivering mental health services which predate the COVID-19 pandemic, and news reports suggest these have proved vital in trying to preserve and boost essential mental health services during this time.[52

  • Access to a Long COVID MDT: restricted access to specialist members of the proposed Long COVID multidisciplinary team, for example physiotherapists [53], could prove challenging in low-resource regions.

This is by no means an exhaustive list, and moving forward the importance of the global healthcare community advocating that appropriate attention is drawn to addressing the long-term effects of COVID-19 for all patients is essential.[54] These needs must be met alongside the unprecedented and ongoing challenges of controlling the spread of COVID-19 and optimising care in the acute phase of the infection. Moving forward, an integrated approach to research and the design of management and rehabilitation services which includes patients, scientists, healthcare professionals, and policy makers together in the discussion is likely to be key.[55

Useful Resources:

Below is a list of some resources related to the long-term effects of COVID-19 which readers may find useful, with several of these resources including their own resource banks. Although divided into resources for healthcare professionals and patients, as discussed above, healthcare professionals may also find several of the resources created by the patient support groups beneficial in increasing their awareness of this evolving condition. If you feel a useful resource is missing please feel free to share the details for this in the comments section below this article.

Emerging Guidance and eLearning for Healthcare Professionals:

Support Groups and Information for Patients:

Patient Support Groups - a collection of some of the groups helping connect COVID-19 survivors and support research into the long-term effects of this infection:

Continue the Discussion:

Join the COVID-19 discussion groups for healthcare professionals on MedShr:


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Article by Dr Ryan Broll, MedShr Open Editorial Team, Medical Education Fellow


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