By Megan Perry
Two million people across the UK are estimated to suffer from long COVID, according to a report from the Office for National Statistics (ONS) published in June 2022. Long COVID is defined as the persistence of symptoms beyond the initial SARS-CoV-2 infection that cannot be attributed to other illnesses, and recovery times vary greatly. Many suffer from acute COVID for only a couple of weeks, yet approximately one in five of those with ongoing long COVID symptoms in the ONS study were first infected more than two years ago. Over half of the long COVID participants experienced fatigue, making it the most common symptom. After this, a myriad of malaises were reported by sufferers, including breathlessness, coughing, ‘brain fog’ (issues with memory and concentration), aches and pains and flu-like symptoms . Yet even for people who haven’t been infected by coronavirus or suffered with long COVID, the pandemic has greatly impacted mental health due to the recurrent isolations .
Despite the vast media attention awarded, long COVID may not be as novel a condition as once thought. In fact, many people suffer from post-viral syndrome (or post-viral fatigue) whilst recovering from an infection. Similar to long COVID, patients primarily experience extreme tiredness along with ‘brain fog’, aches, flu-like symptoms, and many others. Unfortunately, post-viral syndrome isn’t well-understood, and treatments are restricted to lifestyle changes and over-the-counter medicines, such as painkillers. Hence, the comparison between long COVID and post-viral syndrome is useful in validating the predictability of long COVID occurring, but unhelpful in understanding the condition and developing treatments  .
Many suffer from acute COVID for only a couple of weeks, yet approximately one in five of those with ongoing long COVID symptoms in the ONS study were first infected more than two years ago.
The diversity of long COVID experiences, both in terms of symptoms and severity, makes it difficult to find a cure for all cases. Furthermore, developing treatments requires an understanding of the mechanisms behind long COVID to target the root cause, for which there are several theories. Three prevailing ideas were summarised by Jennifer Couzin-Frankelin a recent Science article, ‘Clues to Long COVID’: blood clotting, viral remnants, and an overactive immune system .
Firstly, Couzin-Frankel describes the work of Buonsenso, who studied severe long COVID in children. Buonsenso used SPECT-CT scans to track blood flow to the lungs and observed that this was abnormally low for some of the patients. He suggested that this low flow was caused by microclots (very small blood clots which are difficult to detect), and that these could explain the breathlessness experienced by patients as they had reduced oxygen flow around the body .
Another study by Pretorius et al investigated microclots in blood plasma samples of acute and long COVID patients and found them resistant to fibrinolysis (breaking down of clots) . This was a surprising observation not seen in the microclots of Type 2 Diabetes Mellitus patient plasma samples used by Pretorius et al for comparison. Moreover, the resistance to breakdown could explain the persistent presence of microclots in patients, even months after initial infection. Aside from breathlessness, the reduced blood flow caused by microclotting could explain several symptoms associated with long COVID such as fatigue and brain fog, due to reduced oxygen supply [5, 7-8].
Three prevailing ideas were summarised by Jennifer Couzin-Frankelin a recent Science article, ‘Clues to Long COVID’: blood clotting, viral remnants, and an overactive immune system.
A second potential cause of long COVID symptoms is that fragments of the coronavirus linger in the body after the acute infection and cause harm by a mechanism not yet understood. Zollner et al found a positive correlation between patients experiencing long COVID symptoms and the presence of COVID antigens in their gut – those with symptoms had detectable viral antigens, and those who had recovered did not . As for all the suspected causes of long COVID, however, further clinical trials are required to establish a causal relationship beyond correlation, or that removing antigens would relieve symptoms .
Thirdly, Couzin-Frankel highlights the studies of Phetsouphanh et al who observed high levels of immune signals in long COVID patients several months after initial infection . These signals, such as white blood cell activation and interferon levels (hormones involved in the immune response), cause inflammation that can be beneficial for acute responses to irritants. However, chronic inflammation characterises an overactive immune system and is associated with several conditions such as arthritis and other autoimmune diseases [5, 11-12].
As well as inflammation, a study of 100 long COVID patients found autoantibodies in more than 80% of cases . These are antibodies produced by the immune system that bind to native substances within the body instead of foreign pathogens and have been shown to be precursors to autoimmune diseases . Autoantibodies were also detected inside the microclots investigated by Pretorius et al . Overall, these biomarkers suggest an overactive immune system could be responsible for long COVID symptoms .
The multitude of potential causes for long COVID, and the possibility that multiple causes are working synergistically, provide several targets for drug action. Nonetheless, without a clear prevailing theory, there may be a paradox of choice, in that there are just too many options to choose from. In fact, drug trials such as STIMULATE-ICP in the UK have been delayed while scientists decide which therapies to test . Unfortunately, long COVID trials haven’t received the same emergency expedition as those for acute COVID-19, so the overall process has been much slower, and many trials are ongoing or yet to start.
For example, STIMULATE-ICP confirmed funding in July 2021 but only aimed to recruit patients from July 2022. The trial will test three different therapies for treating long COVID: two antihistamines in combination (Famotidine and Loratadine), an anti-inflammatory drug (Colchicine), and an anticoagulant (Rivaroxaban). The antihistamines will reduce histamine levels, a chemical released by mast cells (a type of white blood cell) that triggers inflammation, so overall having a similar effect to the anti-inflammatory Colchicine . On the other hand, the anticoagulant will target the suspected microclots in long COVID patients to increase blood flow. As it is early in progress, the trial’s full methodologies have not yet been released. However, volunteers in STIMULATE-ICP will be randomly assigned either one of the three therapies, or to have no drugs prescribed at all. The results of each group will be compared to find the most effective treatments for long COVID .
Without a clear prevailing theory, there may be a paradox of choice, in that there are just too many options to choose from. In fact, drug trials such as STIMULATE-ICP in the UK have been delayed while scientists decide which therapies to test.
HEAL-COVID is an ongoing trial in the UK based at over 100 sites, including the John Radcliffe Hospital in Oxford. The trial is comparing the effects of two different therapies against standard hospital care: an anticoagulant (Apixaban) and an anti-inflammatory statin (Atorvastatin). Cholesterol build-up can narrow arteries, and statins work by reducing cholesterol in the blood, so Atorvastatin will aim to increase blood flow as well as reduce inflammation with its anti-inflammatory properties . Although results have not yet been published from these trials, no matter the outcome there is likely to be surplus funding provided until suitable treatments are found for the chronic condition that is affecting so many people across the UK .
Beyond the obvious impact of the pandemic on physical health, another major effect has been psychological. In March 2022, the World Health Organisation (WHO) announced that global rates of anxiety and depression had risen by a quarter in the first year of the pandemic . Given the highly stressful nature of infection and isolation, this figure is unsurprising, although still staggering. Following the WHO announcement, the UK government responded with a £500 million plan to support mental health services . Hopefully, for future pandemics there will be a greater focus on mental health services from the start of lockdowns, not after the fact.
Unfortunately, it may be several years before the mechanisms behind long COVID are fully understood and a cure is found, but there is certainly potential in clinical trials that are ongoing or soon-to-start. Moreover, understanding these mechanisms will unlock knowledge about the immune system that could be vital in future disease outbreaks to prevent a community of over two million people suffering, years after the start of the pandemic.
- NHS. Long-term effects of coronavirus (long COVID) [online].
- Office for National Statistics. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 1 June 2022 [online].
- J Johnson and K Martinez. What to know about post-viral syndrome [online].
- J Seladi-Schulman and D Murrell. Understanding Post-Viral Fatigue [online].
- J Couzin-Frankel. Clue to long COVID [online].
- Medline Plus. Fibrinolysis – primary or secondary [online].
- R Pretorius. Could microclots help explain the mystery of long Covid? [online].
- E Pretorius et al. Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol 20, 172 (2021) [online].
- A Zollner et al. Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Disease. S0016-5085(22)00450-4 (2022). Epub ahead of print, PMID: 35508284; PMCID: PMC9057012 [online].
- C Phetsouphanh et al. Immunological dysfunction persist for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol 23, 210–216 (2022) [online].
- R Pahwa et al. Chronic Inflammation. [online] Treasure Island (FL): StatPearls Publishing (2022) [online].
- Harvard Health Publishing. Playing with the fire of inflammation [online].
- M Rojas et al. Autoimmunity is a hallmark of post-COVID syndrome. J Transl Med 20, 129 (2022) [online].
- WT Ma et al. Development of autoantibodies precedes clinical manifestations of autoimmune diseases: A comprehensive review. J Autoimmun. 2017 Sep;83:95-112 [online].
- STIMULATE-ICP Frequently Asked Questions [online].
- P Fowler and N Ambardekar. What are Histamines? [online].
- NHS. Statins [online].
- HEAL-COVID. About HEAL-COVID [online].
- World Health Organisation. COVID-19 pandemic triggers 25% increase in prevalence of anxiety and depression worldwide [online].
- GOV.UK. Mental health recovery plan backed by £500 million [online].