Long-COVID, post-COVID-19 syndrome
The term Long-COVID was coined at the start of the pandemic by patient groups. They were concerned that some patients would take a long time to recover and any return to work would be slow and may require prolonged adjustments. It was important for everyone to recognize this. It then became a political concept, to apply pressure to Government to support patients who were taking a long time to recover, particularly when they may have contracted COVID-19 in the workplace. It was never a good medical diagnosis and its utility as a diagnosis is becoming more questionable, as the term is too broad, and the range of symptoms encompassed includes conditions unrelated to COVID-19 that are serious and may require urgent investigation and treatment.
Definition
Post-COVID-19 syndrome is defined by NICE(National Institute for Health and Care Excellence, 2024) as:
Signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis.
There is no actual requirement for a positive blood test, just a history consistent with acute COVID-19. Many patients who have been given the diagnostic label Long-COVID have subsequently tested negative for antibodies showing they never had the infection. Some have been given the label when they state they had COVID-19 in 2019, even before it was first identified in China. Some are now developing symptoms several years after having symptoms of acute COVID-19. In many cases the label is being applied even though the patient has another condition that clearly represents an alternative diagnosis.
The NICE guidelines go on to state:
‘It usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body.
In addition to the clinical case definitions, the term 'long COVID' is commonly used to describe signs and symptoms that continue or develop after acute COVID-19. It includes both ongoing symptomatic COVID-19 (from 4 to 12 weeks) and post-COVID-19 syndrome (12 weeks or more)
Symptom prevalence
As a result of this broad definition, any patient who has previously had COVID-19, even many years ago, and now develops a symptom such as chronic or recurrent headache or nausea could have the label ‘Long-COVID.’ This could apply to the great majority of the population if they chose to have the label. For headache disorder alone evidence shows the prevalence to be 52% worldwide (Stovner et al., 2022). The prevalence of chronic widespread pain is 10-15% (Mansfield et al., 2016). The prevalence of breathlessness (dyspnoea) is around 10% (Müller et al., 2023). The prevalence of dizziness is 15-20% (Neuhauser, 2016). The prevalence of chronic cough in Western nations is between 15 and 20% (Abozid et al., 2024). The prevalence of noncardiac chest pain in the community is estimated to be 13% (Ford et al., 2011).
An early study looking at the prevalence of Long-COVID found that around 45% of COVID-19 survivors reported unresolved symptoms at four months (O'Mahoney et al., 2023). A more recent study suggests around 33% of COVID-19 survivors report prolonged symptoms (Dempsey et al., 2024).
The evidence clearly shows that the prevalence of Long-COVID based solely on symptom prevalence is no different to the prevalence of the same symptoms in general populations before or after the COVID-19 pandemic. There is no scientifically logical basis for applying a specific label, Long-COVID, to such symptoms now.
While between a third and half the general population could claim the label Long-COVID as applying to their symptoms, in practice many fewer do so. Studies suggest that between 5 and 10% of individuals seek the specific diagnosis of Long-COVID for their symptoms (Wulf Hanson et al., 2022, O'Mahoney et al., 2023).
Disease prevalence
A much smaller population group is diagnosed with specific pathology related to COVID-19 infection. Evidence demonstrates a wide range of different conditions reported, and this reflects the general medical experience of rare or relatively rare complications of viral infections other than SARS-CoV-2. Examples include pneumonitis, pericarditis, myocarditis, pancreatic harm and new diabetes development, thyroid dysfunction, microclots and thromboembolism with stroke and other end-organ damage, and neurological pathology including encephalitis, mononeuropathies and polyneuropathies.
There has been substantial confusion and misinformation in relation to the prevalence of symptoms versus the prevalence of identifiable pathology. Many studies have identified disease in small numbers and extrapolated their findings to a much wider denominator of people presenting with symptoms. This is sometimes reflected in poor study methodology or in inappropriate assumptions, representing the common failure to distinguish between association and causation alongside poor selection of denominators and control groups. The combination of poor methodology and media hype has led to widespread misunderstanding (Høeg et al., 2023).
Persistent antigens and immune dysfunction
There is evidence for three different types of acute response to infection, the first being a rapid monocyte/MAIT cell response that clears virus without viral proliferation or development of antibodies and no COVID-19 symptoms, the second being a transient infection with early viral clearance, mild symptoms and intermittent positive PCR test. A third group develop a sustained viral infection (Lindeboom et al., 2024).
There is good evidence that some patients experience a prolonged period of viraemia with presence of active virus or viral elements for weeks or months after initial infection (Swank et al., 2022). Antigen was detected in over 70% of patients reporting cardiovascular, systemic, head-eye-ear-nose-throat and musculoskeletal symptoms weeks or months after initial COVID-19 illness. Other studies have shown increased SARS-CoV-2 specific CD4+ and CD8+ T-cell responses and antibody affinity in patients experiencing Long-COVID symptoms suggesting chronic immune activation and presence of persistent SARS-CoV-2 antigen (Opsteen et al., 2023).
A more detailed study of biomarkers has clearly linked different symptoms reported in Long-COVID with specific myeloid inflammation and complement activation markers, with one group associated with cardiorespiratory symptoms, fatigue and anxiety/depression, another with gastrointestinal symptoms, another with cognitive impairment and a fourth was linked with brain-gut axis disturbance (Liew et al., 2024). This was a large study, but some subgroups were relatively small, odds ratios were small, and results need to be validated in future studies. It does suggest that there may be a role for antiviral or immunomodulatory agents in the treatment of some patients with Long-COVID.
It is important to note that while good evidence is emerging to demonstrate some ongoing immune dysfunction, the link between this and symptoms, or severity of symptoms, has not been clearly defined. There is a need for detailed and comprehensive epidemiological studies to clarify the likely causes of symptoms and the prognosis.
Current treatment for Long-COVID
Patients who present with identifiable pathology can be treated in line with standard approaches, for example endocrine abnormalities may be treated with appropriate hormone replacement/supplementation, cardiac abnormalities may require medication to optimize cardiac function, and as noted above the presence of a clear immune dysfunction may respond to immunomodulatory agents.
Many will not have any identifiable pathology or any pathology amenable to treatment. Any therapeutic approach will be primarily supportive. Those who have evidence of substantial physical deconditioning will benefit from a progressive period of rehabilitation that can be supervised by a physiotherapist or occupational therapist. Those who have significant psychological sequelae will benefit from appropriate psychotherapeutic input and may benefit from medication such as an antidepressant or anxiolytic. In most cases simple advice to learn to live with the symptoms, engage with daily activities and work at an appropriate and realistic level should be given on the assumption that many if not most will make a full functional recovery over time.
A common cause of persistent breathlessness is not lung pathology but a learned dysfunctional breathing pattern. This has to be ‘unlearned’ and referral to a respiratory physiotherapist helps the patient settle back into a normal breathing pattern with full functional recovery.
The lack of any clear therapeutic input other than advice and support for rehabilitation has led to many taking the view that ‘nothing can be done’ for Long-COVID, and the view that seeking clinical support is unlikely to lead to any additional benefit.
Prognosis
Many treating clinicians, particularly those involved directly in supporting patients with Long-COVID will note the symptom presentation, the natural symptom prevalence in society, and extrapolate to the conclusion that almost nobody will be symptom-free in the long term. As the symptoms we all experience from time to time are the symptoms associated with Long-COVID, no-one can ‘completely recover’. This is both unhelpful and unscientific, involving an extrapolation from causation to association. Patients who present with Long-COVID should not be told they will never recover, nor that only a very small number will recover. They should be advised that the symptoms they are currently experiencing are very common in the general population and they may well continue to experience them as they would anyway, regardless of whether they had COVID-19 in the past. The expectation is that any pathological sequelae of COVID-19 will settle and recover over time although this can take many months, possibly over a year in some, and new therapeutic approaches could speed this recovery.
Most importantly, there is no evidence that engaging in rehabilitation will cause actual pathological harm to any patient. Trying too hard may well exacerbate symptoms, but this can be managed, following the simple principles of pacing and common sense when gradually increasing activity levels.
There is clear evidence of an association between Long-COVID prevalence and a past history of common mental health disorders (Dempsey et al., 2024). Many patients with Long-COVID will have experienced a significantly traumatic period, whether their own acute illness, or acute illness and possibly the death of relatives and friends, or of working clinically with severely ill patients with COVID-19 or the general social trauma of living through the pandemic. It is important to address any symptoms of post-traumatic stress and to consider patient’s beliefs and behaviours when discussing prognosis and planning any support.
Some patients, as for ME/CFS, may hold very strong views about any association between mental health and their presentation. While it is entirely inappropriate and unscientific to regard psychological factors as having no relevance to presentation or severity of Long-COVID, patients’ views will impact any therapeutic approach and may also give insight into both current presentation and likely prognosis.
Alternative diagnoses
It is essential that other diagnoses are considered before applying the label Long-COVID. We have reached a point where most if not all patients attending their GP could meet the criteria for Long-COVID. Many will have other disease processes, some very serious. There is a risk that, as noted above, they perceive that nothing can be done, so they may delay seeking investigation and support. If they suggest to the GP that they have Long-COVID and are not unduly concerned, the approach to investigation may not proceed at pace but may follow standard waiting times which may represent many months.
Investigations
Patients may well assume they have Long-COVID, however they should have a standard set of investigations undertaken by their GP first, looking primarily for respiratory and cardiac causes of their symptoms, including hypoxaemia or oxygen desaturation on exercise, signs of severe lung disease, and cardiac chest pain. They should have a comprehensive medical history to exclude other conditions such as auto-immune, endocrine, renal and hepatic conditions.
NICE recommends considering full blood count, kidney and liver function tests, C-reactive protein, ferritin, BNP, HBA1c and thyroid function tests. An exercise tolerance test should be considered, usually the one-minute sit to stand test while recording oxygen saturation, breathlessness and heart rate, and for postural symptoms a 3-or 10-minute active stand test. Mental health status should also be assessed to identify those at high risk of self-harm. Once acute or life-threatening complications and alternative diagnoses have been excluded, the patient should be referred to an appropriate service such as a Long-COVID clinic.
Many practitioners are now seeing patients with severe pathology that has nothing to do with past COVID-19 but has been inappropriately linked to it. This includes patients with severe heart failure, pulmonary fibrosis, renal failure, autoimmune disease, endocrine disease including diabetes and neurological disease. In these situations, the assumption that they have Long-COVID is dangerous. We may well be reaching a point where the dangers associated with choosing the label outweigh the utility of a diagnosis.
We should be considering each presentation afresh, investigating empirically and only suggesting that the symptoms may reflect past COVID-19 illness once all potentially serious conditions have been ruled out.
Labelling
The presentation of post-COVID-19 disease is so heterogeneous, and the underlying disease process so different, that we should consider the primary pathology first rather than Long-COVID as a diagnosis. If the patient has developed cardiac dysrhythmia as a result of COVID-19, they have cardiac dysrhythmia not Long-COVID. If they have persistent lung damage, that is what they have, not Long-COVID. If they have gastroparesis, that is the diagnosis not Long-COVID. Treating clinicians will immediately recognize and respond appropriately to a clear clinical label. In some cases, no pathology will be identified, and the symptoms will be identical to those for ME/CFS or fibromyalgia syndrome. In these cases, we should stop using the term Long-COVID for these patients as it has no utility clinically and can negatively influence the therapeutic journey.
Prognosis for Long-COVID for insurance or pensions assessments
Patients with Long-COVID fall broadly into two groups. Those with clearly identifiable pathology or disease and those with no identifiable pathology or disease.
For patients with clearly diagnosed pathology, their prognosis is likely to follow the expected course for any patient with such a post-viral pathology. In some cases, there will be permanent organ damage, with persistently reduced functional capacity. In others there will be a slow progressive improvement that may take months or even over a year in some cases.
Patients with a presentation typical of ME/CFS or fibromyalgia syndrome should follow the expected long-term outcomes for those conditions.
The great majority of patients presenting with symptoms in the longer term will make a good functional recovery.
The recovery trajectory of many months and in a few cases over a year will lead to significant numbers asking about possible ill health retirement. Any assessment should take into account all factors noted above. If there is clear evidence of pathology, that will give an indication of long-term prognosis. In the absence of any obvious pathology, it is important to take a full history to determine whether this represents a pattern of symptoms and GP attendance that predated COVID-19 and the pandemic. It is also important to determine the presence of any significant mental illness that is of relevance to their presentation and engagement with rehabilitation.
As with many cases of medically unexplained symptoms there may be a clear disconnect between reported symptoms and reported function or observed function. Reliability of evidence and history plays a key role in enabling an assessor to determine prognosis.
In some cases, an assessor can determine with reasonable confidence that on balance of probability the applicant will meet the criteria for early payment of pension. In some cases, this will not be possible, and it is not appropriate to recommend ill health retirement in the absence of any clear evidence to support it. Currently there is no evidence that the virus persists for more than a few months in most patients, or for much over a year in any patient. Further epidemiological studies are needed to enable us to give a clear prognosis for those few patients known to have persistent virus antigen and associated immunological response lasting a year or longer. We also need appropriate tests that can demonstrate this.
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