Human challenge studies in the study of infectious diseases
What can deliberately infecting healthy people tell us about infectious diseases? How is this useful for developing treatments, and how do we manage the risks?
What is Long COVID ? How many people are affected? What are the key challenges for diagnosis and treatment? What are the priority areas for research?
In the UK, there has been a high level of sustained infection with SARS-CoV-2, the virus that causes COVID-19, since July 2021. As stated by the Secretary of State for Health and Social Care on 8th December, cases are expected to increase with the Omicron variant. On 7th December 2021, SPI-M-O published a consensus statement on COVID-19, concluding that “there is the potential for a very substantial peak of infections much larger than occurred during the winter wave of January 2021.”
As previously discussed by the Scientific Advisory Group for Emergencies (SAGE) , high prevalence of COVID-19 carries a series of risks, including the risk of hospitalisations, death and Long COVID. A short report on Long COVID prepared by the COVID-19 Longitudinal Health and Wellbeing National Core Study and the Office of National Statistics (ONS) was discussed on 22 July 2021 at the 94th SAGE meeting.
This briefing focuses on the long-term health effects of COVID-19 – also known as ‘Long COVID’. It summarises the evidence on symptoms, prevalence, risk factors and the impact of vaccination. It describes challenges for treatment and management, and Government strategies to tackle this condition.
More details on the additional impact of COVID-19 on mental health and psychiatric symptoms can be found in the POSTnotes on Mental health impacts of the COVID-19 pandemic on adults (July 2021)and Children’s mental health and the COVID-19 pandemic (September 2021).
Most people infected with SARS-CoV-2 experience mild or moderate symptoms that do not require hospitalisation. Some people experience long-term symptoms following infection. This has been called ‘Long COVID’, ‘post COVID-19 condition’, ‘post-acute sequelae of COVID-19’, or ‘chronic COVID syndrome’.
The National Institute for Clinical Excellence (NICE) identifies three different clinical case definitions with regards to SARS-CoV-2 infection:
NICE describes Long COVID as “signs and symptoms that continue or develop after acute COVID‑19”. This definition includes both ongoing symptomatic COVID‑19 and post‑COVID‑19 syndrome. Therefore, according to this definition, Long COVID starts from 4 weeks onwards.
On 6 October 2021, WHO published a clinical case definition of post COVID-19 condition obtained by expert consensus. They defined Post COVID-19 condition as a condition occurring ‘in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms 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 which 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. A separate definition may be applicable for children.’
According to the WHO website, the most common acute symptoms of SARS-CoV-2 infection are fever, cough, tiredness and loss of taste or smell. Less common symptoms reported by WHO include sore throat, headache, aches and pains, diarrhoea, a rash, discolouration of fingers or toes, and red or irritated eyes.
The NHS website states that the main acute symptoms of SARS-CoV-2 infection are a high temperature; a new, continuous cough and a loss or change of smell or taste.
July 2021 data from the ZOE COVID Study app (which monitors self-reported data from more than 4 million users globally) suggested that symptoms vary by variant and vaccination status. For those vaccinated, the most common reported symptoms in July 2021 (with dominant Delta variant) were headache, runny nose, sore throat, sneezing, and persistent cough. For the unvaccinated, they were headache, sore throat, runny nose, fever and persistent cough. Loss of smell (a common symptom at the beginning of the pandemic, when the ‘original’ version of SARS-CoV-2 was circulating) became less common by July 2021.
Long COVID is a complex condition, presenting several symptoms and affecting multiple organs and systems. The National Institute for Health and Care Excellence (NICE) updated its guideline on managing the long-term effects of COVID-19 on 11 November 2021. They reviewed all the evidence available on a series of aspect of Long COVID, including identification, assessment, care and management. They highlighted the lack of certainty of the evidence base, due to the nature of the studies available, which usually consist of surveys filled in by volunteers that are not necessarily representative of the entire population and subject to bias.
The NICE review found that the most commonly reported symptoms of Long COVID were fatigue, shortness of breath, cough, sleep disturbances, anxiety and depression, cognitive impairment, and difficulty concentrating (brain fog). There are several other symptoms associated with Long COVID, including:
The NICE review identified symptoms less commonly reported in children and young people. These included respiratory symptoms (shortness of breath, persistent cough, pain on breathing) and cardiovascular symptoms (palpitations, variations in heart rate, chest pain).
The NICE analysis also noted the high variability of symptoms between 4-12 weeks and 12 weeks+ : fatigue and concentration difficulties were reported consistently over time; cough, sleep disturbances, anxiety and depression were more common at 4-12 weeks rather than 12+ weeks, while hair loss was more common at 12+ weeks. Fatigue and breathing difficulties were also more common among hospitalised patients than non-hospitalised ones.
There is emerging evidence that in Long COVID patients some groups of symptoms often occur together and form ‘clusters’ independent from each other. A study based on an international online survey of over 3000 people with suspected and confirmed COVID-19 found 3 different clusters of symptoms :
The DHSC-funded REACT-2 study (REal-time Assessment of Community Transmission) analysed symptoms at 12 weeks or more in a sample of 508,707 people in England. The results are currently available as a pre-print and are not peer-reviewed yet. Two clusters of symptoms were identified:
The REACT-Long COVID study is a UKRI/NIHR-funded project that aims to follow up for 1.5 years people who were infected of SARS-CoV-2 and compare them with matched controls to better understand this condition, the mechanisms and the long-term symptoms.
The evidence on Long COVID in children and young people is still emerging. A pre-print (not peer-reviewed) from the UK-based CLoCK (Children and young people with Long COVID) study compared the physical and mental health of over 3000 children and young people (aged 11-17-years) after three months of a positive test for SARS-CoV-2 with those of over 3000 peers who tested negative. They found the presence of two different subgroups of children with symptoms at three months:
Several studies have been analysing how likely is to develop long-term COVID-19 symptoms following SARS-CoV-2 infection. Estimates can vary because of methodological differences, including duration of symptoms in consideration, how symptoms are reported in the study and whether participants had a confirmed or suspected case of COVID-19.
Research using self-reported data from around 4000 UK users of the COVID Symptom Tracker app showed that among adults tested positive for SARS-CoV-2, 13·3% had symptoms for at least 4 weeks, 4.5% had symptoms for at least 8 weeks and 2.3% had symptoms for 12 weeks or more. Not -peer reviewed data for the DHSC funded REACT-2 study (REal-time Assessment of Community Transmission) analysed a sample of 508,707 people in England and found that 37.7% of symptomatic adults with confirmed or suspected SARS-CoV-2 infection experienced at least a symptom for 12 weeks or more. 30.5% of them reported this to have a significant effect on their daily life.
An ONS study analysed the prevalence of post-acute COVID-19 symptoms on data collected between 26 April 2020 to 1 August 2021 using different methodologies. When considering self-reported Long COVID in people with a confirmed infection, the study reported that 11.7% of participants would describe themselves as experiencing Long COVID at 12 weeks after infection. This figure increased to 17.7% when considering only symptomatic cases in the acute phase of infection.
A recent report systematically analysing several international studies found that between 3 and 6 months a median of 26% (2-62%) non-hospitalised patients still experienced symptoms and a median of 57% (13-92%) hospitalised patients still experienced symptoms following SARS-CoV-2 infection.
In England, there has been a sustained rate of new cases between children and young people aged 0-19 years, and it is currently at around 700 new cases per 100,000 people in this age group. The proportion of children with SARS-CoV-2 who go on to experience long-term symptoms is generally lower than adults. According to research using data from over 1,700 UK school-aged children and young people (age 5–17 years) collected through of the COVID Symptom Tracker app, 4.4% of children and young people infected with SARS-CoV-2 experienced symptoms for more than 4 weeks, and 1.8% experienced symptoms for at least 8 weeks.
A pre-print (not peer-reviewed) from the UK-based CLoCK (Children and young people with Long COVID) study compared symptoms of around 3000 children and young people (aged 11-17-years) who tested positive for SARS-CoV-2 with those of around 3000 children and young people with a negative test. At three months, 14% more children and young people who tested positive had three or more symptoms of ill health, including tiredness and headaches.
On 2 December 2021, the Office for National Statistics (ONS) reported the latest results of its UK Coronavirus (COVID-19) Infection Survey, with data up to 31 October 2021. It estimated that around 1.2 million people in the UK (including around 77,000 children aged 2-16 and around 134,000 people between 17 and 25 years old) were experiencing self-reported Long COVID (defined as ‘symptoms lasting for more than 4 weeks after a suspected infection that are not explained by something else’). This represents 1.9% of the overall population and it is consistent with previous data released from the ONS (which included cases until 2 October 2021).
In the ONS Survey, around 1 in 5 respondents reporting long lasting symptoms had (or suspected they had) COVID-19 less than 12 weeks previously, while around 7 in 10 respondents had (or suspected they had) COVID-19 at least 12 weeks previously. This includes 1 in 3 respondents who had (or suspected they had) COVID-19 at least one year previously.
The ONS estimated that the percentage of people suffering Long COVID in the overall population (i.e., not only those infected) by age group are:
The biological mechanisms underpinning Long COVID remain poorly understood. There are different mechanisms that could probably explain the variety of symptoms. These could be different in different people or could co-exist in individuals. These mechanisms include the possibility that SARS-CoV-2 persist in reservoirs in the body; defects in the immune response (including autoimmunity) and presence of microscopic blood clots.
The latest NICE evidence review for risk factors identified a series of risk and protective factors associated with Long COVID, although the evidence base is uncertain. Being of female sex, having poor pre-pandemic health and poor general health, suffering from asthma and being overweight or obese have been identified by the NICE review as risk factors of developing Long COVID. Being a non-white ethnic minority, in particular of South Asian origin has been identified instead as a protective factor.
The latest NICE evidence review also assessed risk factors in children and young people based on very few studies available. NICE found that older children (aged 6-18) are more likely to suffer from Long COVID than younger ones (aged 2-5). Risk factors associated with developing Long COVID included allergies, asthma, eczema and one or more pre-existing conditions.
The evidence on how effective COVID-19 vaccines are in protecting against developing Long COVID is still emerging. Research using self-reported data from 1.2m UK users of the COVID Symptom Tracker app (aged 18-60+) found that two vaccine doses reduced by half the risk of developing symptoms for more than 4 weeks (overall, 5% in double vaccinated vs 11% in not vaccinated). There is uncertainty in these figures emerging from the self-reported nature of the data and the fact that the study included more women than men and less individuals from deprived areas.
A pre-print (not peer reviewed study) compared the health records of around 10,000 vaccinated individuals in the US who got infected at least 2 weeks after receiving their vaccine with matched controls. The study found that vaccination led to a reduction of many (but not all) symptoms of Long COVID, including fatigue, pain and loss of smell. A limitation of this study is its reliance on health records, which may not reflect milder symptoms.
At the time of writing, there is no evidence available with regards to the impact of the booster programme or vaccination in children on reducing Long COVID rates in adults and children respectively.
The impact of vaccination on people suffering of ongoing Long COVID symptoms is uncertain. A study led by the patient group Long COVID SOS (not peer reviewed) analysed the responses of 900 patients with Long COVID who participated in an online questionnaire. 56.7% of patients reported improvement in symptoms following vaccination, 18.7% a deterioration, and 24.6% no change. The small sample size, the lack of control groups and the observational nature of this study are key limitations of this work.
An ONS study analysed the relationship between COVID-19 vaccination and self-reported Long COVID between 3 February 2021 and 5 September 2021 in 28,356 people in the UK (aged 18 to 69 years, 55.6% female), who caught SARS-CoV-2 before being vaccinated. The study reported a sustained improvement of Long COVID symptoms after the second vaccine dose during a median follow up period of 67 days. The observational nature of the study and the short follow up period are the main limitations of this work.
The NICE review concluded that there are treatments available to manage some of the symptoms of Long COVID (for instance, antihistamines can be used to treat skin rashes). However, there is still no evidence on effective pharmacological treatments for the condition.
A rapid narrative review focused on management of Long COVID in primary care in the UK recommended a series of actions in these settings, including symptoms treatment ( e.g., using paracetamol against fever), control of long-term conditions and empathy. Patient self-management was also recommended, including daily monitoring of blood oxygen levels, attention to general health, rest and relaxation.
There are a series of self-management tools available for patients, with advice on managing common symptoms, such as Your COVID Recovery and NHSinform websites.
NICE updated its guideline on managing the long-term effects of COVID-19 on 11 November 2021.
There are ongoing challenges for the medical profession in diagnosis and treatment of Long COVID. Many of these are still in their infancy, as more time is needed understand how long this condition lasts for. Given that Long COVID is a multisystemic condition, there is agreement among medical professionals that treatment and management of Long COVID requires a multidisciplinary team, complemented with holistic care pathways, investigation of specific complications, management of potential symptom clusters, and tailored rehabilitation. Other key aspects identified for a multidisciplinary model of care for Long COVID included access to social work and welfare support and coordination between primary care and more specialised care.
Some doctors reported the lack of clear communication about what clinical coding to use to record Long COVID in primary care, as well as the need for more resources in primary care to ensure doctors have the necessary time to care for Long COVID patients. Other challenges include managing Long COVID together with other diseases (including diabetes, heart disease and kidney disease); a limited understanding of the biological mechanisms behind Long COVID (making it harder to find treatments) and a lack of early diagnostic tools to identify it. Some researchers highlighted that the fact that a Long COVID diagnosis is based on exclusion of other causes (rather than on a diagnostic test) creates challenges for patients and carers.
There are uncertainties about the impact of specific variants on the risk of developing Long COVID. For instance, the current trend of Long COVID is unknown, as many people infected by the Delta variant were vaccinated (in contrast to those who developed Long COVID more than a year ago, when the vaccinations were not available).
There are also uncertainties due to the spread of the Omicron variant. Robust models on how many cases of Long COVID are expected with Omicron are not yet available and it will take months (i.e., more than 12 weeks from the infection) to observe the effect of Omicron on Long COVID prevalence. There is still uncertainty about the impact of the Omicron variant on COVID -19 rates and severity, as well as how well vaccines work against Omicron and its symptoms.
On 24th November 2021, SPI-M-O published a consensus statement on COVID-19 (before the emergence of the Omicron variant).They concluded that it will take a long time for COVID-19 to become endemic and that this will be dependent on how long immunity lasts and on vaccination and boosting policies. In an endemic scenario, the population impact of Long COVID is largely unknown.
There is emerging evidence on the long-term health impact of COVID-19 on the population from the first year of the pandemic. A paper prepared by the Department of Health and Social Care and the ONS on this topic was discussed at the 95th SAGE meeting on 9 September 2021. It estimated the impact of COVID-19 on the population in terms of lost Quality Adjusted Life Years (QALYs), with 1 QALY representing 1 year of life in perfect health. The analysis showed that between April 2020 and April 2021 females lost 43,000 QALYs due to COVID-19 related illness, compared to 38,000 QALYs lost in males. Out of these, there were 16,000 and 14,000 respectively QALYs lost due to the ongoing phase of COVID-19 (4 weeks -12 weeks) and 13,000 and 11,000 respectively QALYs lost due to illness caused by COVID-19 from 12 weeks to a year.
In March 2021, the World Health Organisation published its report In the Wake of the Pandemic: Preparing for Long COVID, outlining how countries could develop policies to respond to Long COVID. They recommended action to address the wider consequences of Long COVID, such as employment rights, sick pay policies, and access to benefit and disability benefit packages. An Academy of Medical Sciences report also highlighted the need for equitable employment and educational support to reduce the risk of widening health inequalities.
There is evidence that Long COVID could prevent people from returning to work. The Trades Union Congress (TUC, which represents more than 5.5 million working people in England and Wales) called for the recognition of Long COVID as a disability and COVID-19 as an occupational disease in July 2021. The British Medical Association called for Long COVID to be recognised as occupational disease in September 2021.
Guidance for healthcare professionals on return to work for patients with long-COVID was published by the Faculty of Occupational Medicine of the Royal College of Physicians. Supporting patients with Long COVID return to work requires first understanding their symptoms and how these impact their work. Adjustments could include reduced hours, flexitime, or special equipment.
There are still a series of unknowns related to Long COVID that need to be addressed to adequately shape a public health response. The main recommendations for research following the latest NICE review focused on a better understanding of interventions (e.g., medical treatments; social prescribing and community support; effectiveness of different interventions for specific population groups and the role of exercise) and of prevalence (especially in the vaccinated population).
Other recommendations for research included the development of tools able to identify Long COVID and predict its emergence, better understand of the biological mechanisms and further study of this condition in children, young people, pregnant women and older people. These priorities are shared among international stakeholders, including researchers, funders and patient groups. Other researchers call for better study design, including clearer patient inclusion criteria and clearer definitions of the condition under investigation. Global surveillance of this condition, including in Low- and Middle-Income Countries is another priority identified.
Finally, an important unanswered question is the relationship between Long COVID and other conditions, including the myalgic encephalitis/ chronic fatigue syndrome (ME/CFS).
As July 2021, there were 121 Long COVID research projects across the world to address these unknowns, supported by over $200m of funding investments.
In October 2020, the NHS announced a 5-point plan to support Long COVID patients. Outcomes included the NICE updated guidelines on managing the long-term effects of COVID-19, the establishment of 89 Post-COVID Assessment Clinics in England, the creation of the online rehab service ‘Your Covid Recovery‘, 15 National Institute for Health Research (NIHR) funded research projects across the UK and the establishment of the NHS England Long COVID taskforce.
In June 2021, the Government announced the NHS Long COVID Plan for 2021/22. Commitments included investments in Long COVID treatment and rehabilitation and in enhanced general practice; care coordination; the establishment of 15 Post-COVID assessment children and young people’s hubs; the development of standard rehabilitation pathways and focus on equity of access, outcomes and experience.
In its COVID-19 Response: Autumn and Winter Plan 2021, the Government reiterated its commitment to supporting Long COVID research and expand NHS services.
Some public health experts identified a series of challenges underpinning the health system response to Long COVID in England, including service delivery, information management, financing and the long-term sustainability of the increased demands on the NHS.
POST would like to thank Dr Nisreen Alwan MBE (Associate Professor in Public Health, University of Southampton) who acted as external peer reviewer in preparation of this article.
Photo by Mufid Majnun on Unsplash
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