An unusual case of a Long Covid patient’s legs turning blue after 10 minutes of standing highlights the need for greater awareness of this symptom among people with the condition, according to new research published in theLancet.
The paper, authored by Dr Manoj Sivan at the University of Leeds, focuses on the case of one 33-year man who developed with acrocyanosis – venous pooling of blood in the legs.
A minute after standing, the patient’s legs began to redden and became increasingly blue over time, with veins becoming more prominent. After 10 minutes the colour was much more pronounced, with the patient describing a heavy, itchy sensation in his legs. His original colour returned two minutes after he returned to a non-standing position.
The patient said he had started to experience the discolouration since his COVID-19 infection. He was diagnosed with postural orthostatic tachycardia syndrome (POTS), a condition that causes an abnormal increase in heart rate on standing.
Dr Sivan, Associate Clinical Professor and Honorary Consultant in Rehabilitation Medicine in the University of Leeds’ School of Medicine, said: “This was a striking case of acrocyanosis in a patient who had not experienced it before his COVID-19 infection.
“Patients experiencing this may not be aware that it can be a symptom of Long Covid and dysautonomia and may feel concerned about what they are seeing. Similarly, clinicians may not be aware of the link between acrocyanosis and Long Covid.
“We need to ensure that there is more awareness of dysautonomia in Long Covid so that clinicians have the tools they need to manage patients appropriately.”
Long Covid affects multiple systems in the body and has an array of symptoms, affecting patients’ ability to perform daily activities. The condition also affects the autonomic nervous system, which is responsible for regulating blood pressure and heart rate.
Acrocyanosis has previously been observed in children with dysfunction of the autonomic nervous system (dysautonomia), a common symptom of post-viral syndromes.
Previous research by Dr Sivan’s team has shown that both dysautonomia and POTS frequently develop in people with Long Covid.
Dysautonomia is also seen in a number of other long-term conditions such as Fibromyalgia and Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome or ME.
Dr Sivan said: “We need more awareness about dysautonomia in long term conditions; more effective assessment and management approaches, and further research into the syndrome. This will enable both patients and clinicians to better manage these conditions.”
The research is the latest work by the team in the field of autonomic medicine. Other developments include a home test for people with symptoms of autonomic dysfunction in conditions such as long COVID, chronic fatigue syndrome, fibromyalgia, and diabetes 1 and 2, where people experience dizziness or blackouts.
Researchers from King’s College London have found that people with longer-term COVID symptoms including brain fog showed reduced performance in tasks testing different mental processes – up to two years after infection with the virus, according to results published in the journal eClinicalMedicine.
Researchers examined whether COVID infection affected performance in two rounds of online cognitive testing that took place in 2021 and 2022. Data was collected for over 3000 participants of the COVID Symptom Study Biobank study, across 12 tasks that tested memory, attention, reasoning, processing speed and motor control.
The participants whose test scores were most affected by COVID were those who had experienced symptoms related to the virus for 12 weeks or more. In these people, the effect of COVID on test accuracy was comparable in size to the effect of a 10-year increase in age.
There was no significant improvement in these test scores between the two rounds of testing, which took place nine months apart. By the second round of testing, the average time since participants’ initial COVID infection was almost two years.
The researchers then separated participants by whether they felt fully recovered following COVID infection. People who felt fully recovered after COVID infection performed similarly to those who had not had the virus at all. In contrast, participants who did not feel fully recovered after infection had lower task accuracy scores on average.
Lead author Dr Nathan Cheetham, a Senior Postdoctoral Data Scientist at King’s College London said:
“Our findings suggest that, for people who were living with long-term symptoms after having COVID, the effects of the coronavirus on mental processes such as the ability to recall words and shapes are still detectable at an average of almost two years since their initial infection.
“However, the result that COVID had no effect on performance in our tests for people who felt fully recovered, even if they’d had symptoms for several months and could be considered as experiencing ‘long COVID’, was good news. This study shows the need to monitor those people whose brain function is most affected by COVID-19, to see how their cognitive symptoms continue to develop and provide support towards recovery.”
Professor Claire Steves, a Professor of Ageing and Health at King’s College London, added:
“We used sensitive tests to measure speed and accuracy across a range of brain challenges. This study shows that some individuals have measurable changes in these tests after COVID-19 going on for nearly two years. The fact remains that two years on from their first infection, some people don’t feel fully recovered and their lives continue to be impacted by the long-term effects of the coronavirus. We need more work to understand why this is the case and what can be done to help.”
Research led by the University of Bristol has found that long COVID is not caused by an immune inflammatory reaction to COVID. Emerging data shows that immune activation may persist for months after contracting COVID. In this new study, published in eLife, researchers wanted to find out whether persistent immune activation and ongoing inflammation response could be the underlying cause of long COVID.
To investigate this, the Bristol team collected and analysed immune responses in blood samples from 63 patients hospitalised with mild, moderate or severe COVID at the start of the pandemic and before vaccines were available. The team then tested patients’ immune responses at three months and again at eight and 12 months post hospital admission. Of these patients, 79% (82%, 75%, and 86% of mild, moderate, and severe patients, respectively) reported at least one ongoing symptom with breathlessness and excessive fatigue being the most common.
Dr Laura Rivino, the study’s lead author, explained: “Long Covid occurs in one out of ten COVID cases, but we still don’t understand what causes it. Several theories proposed include whether it might be triggered by an inflammatory immune response towards the virus that is still persisting in our body, sending our immune system into overdrive or the reactivation of latent viruses such as human cytomegalovirus (CMV) and Epstein Barr virus (EBV).”
The team found patients’ immune responses at three months with severe symptoms displayed significant dysfunction in their T-cell profiles indicating that inflammation may persist for months even after they have recovered from the virus. Reassuringly, results showed that even in severe cases inflammation in these patients resolved in time. At 12 months, both the immune profiles and inflammatory levels of patients with severe disease were similar to those of mild and moderate patients.
Patients with severe COVID were found to display a higher number of long Covid symptoms compared to mild and moderate patients. However, further analysis by the team revealed no direct association between long COVID symptoms and immune inflammatory responses, for the markers that were measured, in any of the patients after adjusting for age, sex and disease severity.
Importantly, there was no rapid increase in immune cells targeting SARS-CoV-2 at three months, but T-cells targeting the persistent and dormant Cytomegalovirus (CMV) – a common virus that is usually harmless but can stay in your body for life once infected with it – did show an increase at low levels. This indicates that the prolonged T-cell activation observed at three months in severe patients may not be driven by SARS-CoV-2 but instead may be “bystander driven” ie driven by cytokines.
Dr Rivino added: “Our findings suggest that prolonged immune activation and Long COVID may correlate independently with severe COVID. Larger studies should be conducted looking at both a larger number of patients, including if possible vaccinated and non-vaccinated COVID patients, and measuring a larger range of markers and cytokines.
“Understanding whether inflammation and immune activation associate with Long COVID would allow us to understand whether targeting these factors may be a useful therapy for this debilitating condition.”
A new UK study has found that fatigue is the most significant symptom for long COVID patients, and can affect quality of life more than some cancers. The research, published in BMJ Open, examines the impact of long COVID on the lives of over 3750 patients who were referred to a long COVID clinic and used a digital app as part of their NHS treatment for the condition.
Patients were asked to complete questionnaires on the app about how long COVID was affecting them – considering the impact of long COVID on their day-to-day activities, levels of fatigue, depression, anxiety, breathlessness, brain fog, and their quality of life.
The researchers, from UCL and the University of Exeter, found that many long COVID patients were seriously ill and on average had fatigue scores worse or similar to people with cancer-related anaemia or severe kidney disease. Their health-related quality of life scores were also lower than those of people with advanced metastatic cancers, like stage IV lung cancer.
Overall, the team found that the impact of long COVID on the daily activities of patients was worse than that of stroke patients and was comparable to that of patients with Parkinson’s disease.
Dr Henry Goodfellow, who co-led the study alongside the late Professor Elizabeth Murray (both UCL Institute of Epidemiology & Health), said: “Up to around 17% of people who get COVID go on to develop long COVID *. However, the impact of the condition on patients’ day-to-day lives isn’t fully understood.
“Our results have found that long COVID can have a devastating effect on the lives of patients – with fatigue having the biggest impact on everything from social activities to work, chores and maintaining close relationships.”
Not only does long COVID negatively impact the lives of patients on an individual level, the researchers also believe that it could have a significant economic and social impact on the country.
In order to be referred to a long COVID clinic, a patient must have had symptoms in keeping with long COVID for at least 12 weeks after an acute infection.
Over 90% of long COVID patients using the app were of working age (18-65) and 51% said they had been unable to work for at least one day in the previous month, with 20% unable to work at all.
Meanwhile, 71% of patients were female. As working-age women make up a majority of the health and social care workforce, the impact of long COVID on their ability to function may add additional pressures to already stretched services.
Dr Goodfellow said: “We hope that a greater understanding of the symptoms and impact of long COVID in these patients will help the NHS and policymakers to target limited resources by adapting existing services and designing new ones to better meet the needs of patients with long COVID .”
Alongside fatigue, long COVID patients typically experience breathlessness, anxiety, depression and brain fog. This is the first study to report on the impact of the condition on day-to-day functioning and health-related quality of life in patients who have been referred for specialist rehabilitation in long COVID clinics across England.
Dr Goodfellow said: “Our findings show that fatigue should be an important focus for clinical care and the design of rehabilitation services.
“Post-COVID assessment services should consider focusing on assessing and treating fatigue to maximise the recovery and return to work for sufferers of long COVID .”
In a new entry to the growing list of lasting complications from COVID infection, a large German cohort study of over 600 000 COVIDpatients indicates that new autoimmune conditions may result from previous COVID infection. The findings, which are awaiting peer review on the MedRxiv preprint server, show that the odds of new autoimmune conditions appear to increase in line with the severity of COVID infection.
After the acute phase of infection, some people may develop long-lasting symptoms, known as post-COVID, which are consistent with COVID infection and last more than 12 weeks. Most studies to date have focused on symptoms that partly wane over time. Many studies examined a small selective sample of patients, and only a few studies included a control group or information on chronic health conditions, such as SARS-CoV-2 infection.
Compared to post-COVID emergence of cardiovascular and other diseases, autoimmune diseases are less discussed in the literature, although autoantibodies could be found in patients after SARS-CoV-2 infection. So far there is limited evidence on newly manifested autoimmune diseases after an infection based on several case reports and one recent cohort study using UK health record data. In addition, COVID itself has some similarities with systemic autoimmune rheumatic diseases, which could make diagnosis difficult.
The researchers selected a cohort from German routine health care data, identifying individuals with polymerase chain reaction (PCR)-confirmed COVID through December 31, 2020. Patients were matched 1:3 to control patients without COVID. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyse the onset of autoimmune diseases during the post-acute period. The researchers calculated the incidence rates (IR) per 1000 person-years for each outcome and patient group, and estimated incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding COVID.
In total, 641 704 patients with COVID were included. When comparing the incidence rates in the COVID and matched control groups, the researchers found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune disease of the vasculitis group. Patients with a more severe course of COVID were at a greater risk for incident autoimmune diseases. These risk increases were as follows:
41% higher risk of Grave’s disease
42–45% higher risk of rheumatoid arthritis
25% higher risk of type 1 diabetes
27-29% higher risk of Crohn’s disease
The researchers concluded that SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection.
“I think I’m in trouble,” came the message through to Professor Veronica Ueckermann one evening during the first surge of COVID-19 in South Africa in the winter of 2020. It was a distressed call made by a 48-year-old theatre nurse who worked alongside Ueckermann in the ICU frontline. Ueckermann, who is also a professor of internal medicine at the University of Pretoria and an ICU specialist, shifted into high gear with other doctors to save their colleague who was diagnosed with COVID-19.
They succeeded.
But what they didn’t know then was that months later the nurse would be ailing from ongoing medical symptoms put down to the catch-all of long-COVID.
“It’s a case study, but it was also very close to my heart,” says Ueckermann, who has become a specialist and researcher on the long-term effects of COVID. She recently presented on long-COVID during a webinar of the South African Academy of Family Physicians. “The nursing sister had numerous comorbidities, including a raised BMI, diabetes, hypertension, and asthma. When her symptoms didn’t get better, the hospital just wanted to have her medically boarded because they couldn’t be sure when she would be well enough to work again,” says Ueckermann.
She is cautious too, pointing out that there’s still little definitively known about long-COVID and new research is only in its infancy. Much of the difficulty lies in the wide-ranging symptoms and how individuals are affected. There are also varying recovery times, different underlying conditions and susceptibilities, and the reality that many people are simply not diagnosed. It makes the term “long-COVID” an umbrella term for everything from brain fog or mental confusion and fatigue to depression and shortness of breath and chest pains. Others also describe general body aches and continued loss of smell and taste.
The post-COVID condition
In October 2022, the World Health Organization (WHO) released a factsheet that states that between 10% and 20% of people who are diagnosed with COVID-19 continue to have symptoms beyond three months of first getting ill and develop what the WHO refers to as post-COVID condition. Many more people say symptoms plague them still even after nearly two years.
“The condition can be debilitating, causing disabling symptoms and functional deficits. It can significantly impact people’s ability to work, engage and participate fully in family and community life. Mental health effects can directly result from long-COVID, but may also develop due to prolonged suffering and distress caused by the condition,” reads the WHO factsheet.
The WHO’s recommended treatment, however, is non-specific, stating: “Post-COVID-19 condition can be supported with help from their families, peers, employers, and the community and they can also benefit from tailored rehabilitation.”
According to the National Institute for Communicable Diseases (NICD), “Every long-COVID patient is different, as such, every patient will need treatment specific to their symptoms which can be managed by their family doctor or clinic. There are no drugs to prevent long-COVID. Long-COVID is not a contraindication to vaccination, and COVID-19 vaccination may even sometimes improve long-COVID symptoms. Long-COVID is treated by slow, stepwise rehabilitation, and appropriate management of symptoms.”
Greater awareness and education needed
Ueckermann agrees with the WHO’s call for greater awareness and education so patients feel heard and supported. Many people resort to joining online support groups through platforms like Facebook. They share their challenges and stories and give each other support when they feel misunderstood and frustrated that they can’t get well and doctors can’t help. Ueckermann says there needs to be help for patients’ individual needs because not finding solutions will add to mounting pressure on the healthcare system.
“Because of COVID disruptions, many cancers are now presenting at later stages. There are cases of TB and other illnesses that were neglected. And now we have long-COVID that requires diagnosis after diagnosis for exclusion so all of this drives up costs,” she says.
lung There are other associated costs for people who cannot work or are performing sub-optimally trying to work while feeling unwell. Children affected by long-COVID do worse at school and lose interest in their sports and other activities that they used to enjoy, she says.
Last year, Spotlight reported on a dedicated long-COVID clinic at Groote Schuur Hospital in Cape Town. As far as we could establish, such specialised long-COVID clinics are very rare in South Africa.
“Long-COVID remains inaccurately defined and as a result, standard treatment guidelines for the condition as a whole have not yet been developed,” says Foster Mohale, Spokesperson for the National Department of Health. “However, standard treatment guidelines to address the symptoms and conditions associated with long-COVID are in place,” he says. “These guidelines guide assessment and treatment, and provide criteria for referral from primary healthcare to more specialised services.”
Mohale adds that the burden of disease is of “enormous concern and needs to be better understood and quantified”. But says the department’s data shows that visits by adults to public sector primary healthcare facilities remain below pre-pandemic levels, which suggests that any increase in the burden of disease has not resulted in an increased burden on health services. He also emphasises the need to have up-to-date vaccinations, adding that “people who are vaccinated are less likely to develop long-COVID”.
Research ongoing
Ueckermann says it’s a positive development that as awareness is growing, so are studies, including studies by the Medical Research Council and many of the country’s universities. She says scientists are looking at everything from the role of green tea extracts and the use of SSRIs (Selective serotonin reuptake inhibitors) that are commonly used to treat depression.
“These are all ongoing studies, so we have to wait to see the data coming through but it’s promising that everyone is trying to understand exactly what this long-COVID is and the most important thing is that we continue making this a greater area of priority in healthcare,” she says. It matters for the growing number of patients, or for her colleague who she says still needs help to get from “doing better,” to fully recovered.
A first-of-its-kind study published in Scientific Reports has investigated how the immune system of elite student-athletes responded to the COVID virus. Unlike older adults with comorbidities, American Football players who were diagnosed with COVID were able to have their immune system back to its baseline after their CDC-recommended isolation period.
“When COVID really started moving out of control, we met with Neil Johannsen, an exercise physiologist at LSU, and the athletic trainers Derek Calvert and Jack Marucci, and we discussed what we could do to make sure our athletes remained healthy. We especially wanted to make sure that athletes were not at risk for secondary infections when they came back from isolation,” said Guillaume Spielmann, associate professor in LSU’s School of Kinesiology.
Isolation effective after COVID infection
“When the idea started for the research, we discussed why not turn something negative into a positive, and assist with the research to find some answers. If we can do things to understand the virus better, let’s do it,” said Jack Marucci, LSU’s Director of Athletic Training. “The student-athletes were willing to be a part of it.”
During that time at the start of the COVID pandemic, the CDC had recommended 14 days of isolation.
“There was a lot unknown during this time. We are looking at a population that are extremely close to each other during plays and during games. We wanted to make sure that since they are literally face-to-face with other players, that their salivary defences, their oral defences were pretty much intact and that that part of their immune system was not affected by the disease; that there were no long-lasting effects of the disease,” Assoc Proff Spielmann said.
Saliva samples were collected from 29 student-athletes in 2020, before a COVID vaccine. Fourteen were COVID positive and 15 had no history of infection. Of the 14, only six reported mild symptoms from the virus, the other eight were asymptomatic throughout the isolation period.
“Salivary immunity is extremely important to ensure that people don’t contract secondary infections, so when athletes are coming back we need to make sure they are as healthy as can be. We found that the isolation period was sufficient to restore the athletes’ salivary immunity to the level seen in non-infected players,” Assoc Prof Spielmann said.
Safely return to play after COVID
These findings suggested the student-athletes could safely return to practice and play football without a risk of secondary infection; that their immune system wasn’t at risk when playing the close contact sport.
“I was worried a bit about long-haulers and other more significant outcomes like the concerns for the development of myocarditis. Engaging in athletic activities at an elite level can be stressful on the body and you would want to arm yourselves with the best scientific information to help understand potential outcomes. This data helped to validate some of these decisions that were made. Providing a safe environment for your student-athletes is paramount and this helped that process along,” said Shelly Mullenix, LSU’s Senior Associate Athletics Director for Health & Wellness.
For this study, three graduate students also participated in the research.
“This kind of access is unique in Division I sports. You typically don’t have access to football players, so the fact that we have access is hugely instrumental as well,” Assoc Prof Spielmann said. “LSU is a great place for this field.”
“I think this COVID research is something that we are really proud to be a part of and contribute to finding answers to such a devastating virus,” Marucci said.
Assoc Prof Spielmann, an immunologist, researches the impact of stress on the immune system of elite and tactical athletes, including astronauts and fire fighters. But this study isn’t the first for Spielmann and LSU Athletics. They have worked together to study psychological and physiological health, along with performance measures in other student-athletes and sports teams. A new study will take a closer look at female athletes’ mental, physiological and immune resilience to stress.
A US study published in JAMA Network Open found that COVID was associated with a 4% increase in use of health care services across that country over the six months after initial infection.
Long COVID is known to affect some COVID patients long after symptoms of the acute infection had subsided. The typical clinical symptoms in long COVID are tiredness, dyspnoea, fatigue, brain fogginess, autonomic dysfunction, headache, persistent loss of smell or taste, cough, depression, low-grade fevers, palpitations, dizziness, muscle pain, and joint pains. This study showed that the greatest increase in encounters for these patients was in virtual visits, followed by emergency department visits.
“This study showed us that, in terms of the number of follow-up visits, a substantial amount of health care utilisation occurs in the six months following the acute stage of SARS-CoV-2 infection, which highlights the potential for COVID to exert an ongoing demand on health care organisations,” said epidemiologist Sara Y. Tartof, PhD, one of the study’s lead authors. “A 4% increase in encounters applied across a large population is a large number of visits associated with substantial cost. The absolute number is big. In this case, it was over 27 000 extra encounters among the eight health care organisations included in this study.”
Dr Tartof added: “On a broader scale, this study will help health care organisations develop their long-term strategic plans to meet patients’ needs following COVID infection.”
This study included patients of all ages from eight large integrated health care organizations across the US who completed a COVID diagnostic test between March 1 and November 1, 2020. Patients were matched on age, sex, race, ethnicity, site, and date of COVID test, and were followed for 6 months. The final matched study group consisted of 127 859 patients who tested positive for COVID-19 with an equal number testing negative.
Overall coronavirus infection was associated with a 4% increase in health care use over six months, predominantly for virtual encounters, followed by emergency department visits.
COVID-associated health care encounters for 18 conditions remained elevated 6 months from the acute stage of illness, with the largest increase in COVID-related utilisation including:
lingering COVID
alopecia, also known as hair loss
bronchitis
pulmonary embolism or deep vein thrombosis
difficulty breathing
In total, extra health care use associated with the effects of COVID infection consisted of 212.9 additional encounters per 1000 patients with COVID.
The study is one of the largest and most comprehensive studies of post-COVID utilisation among children under age 17.
COVID-positive children experienced increased health care use over six months for pulmonary embolism or deep vein thrombosis; irregular heartbeat; difficulty breathing; and ear, nose, and throat disorders.
“With complete data from all care settings across large integrated health care organisations, this study represents one of the largest and most comprehensive studies of post-COVID conditions to date,” said epidemiologist Debbie Malden, DPhil, another lead author.
Professor Resia Pretorius sounds rushed when Spotlight first tracks her down by phone at Heathrow Airport outside London. She is about to board a plane to South Africa after attending a conference, meetings, and symposia in the United Kingdom, all with the purpose of unravelling the complexity of long COVID and how to treat it.
There is no global consensus among researchers and clinicians on a definition for long COVID, there is no adequate diagnostic test for the debilitating condition, and the causes of patients progressing to long COVID are, at this stage, theoretical.
However, Pretorius who heads the Department of Physiological Science at the University of Stellenbosch remains upbeat. Her research group is the first to have reported evidence of inflammatory microclots in blood samples from individuals with long COVID, potentially solving an important piece of the long COVID puzzle.
She says scientific collaboration is intensifying to find answers to long COVID which affects 43% or 100 million people globally post-infection, according to a meta-analysis and systematic review.
Later speaking from Stellenbosch, Pretorius describes herself as a “lab person” who has been trying to find the cause of long COVID since 2020. “I have always been passionate about research. Now, I am working with clinicians and researchers in the UK, the USA, and other parts of the world. I am too worried to miss anything so I am at all of these meetings. There are 40 to 50 researchers globally who talk to each other regularly. We are going to crack this I know. We just have to.”
Causes of long COVID
As explained in a recent article in the journal Science, there are three leading theories scientists are pursuing in an attempt to decipher the effects of post-COVID-19 infection – which leads to an array of symptoms, including shortness of breath, fatigue, headaches, palpitations, and impairments in mental health and cognition or brain fog.
One theory is that SARS-CoV-2 stubbornly persists in the body, even after the acute infection passes. Studies have shown that the virus lingers in a wide range of body sites, especially in the nerves and other tissues.
Another theory based on blood samples from COVID-19 patients reveals an immune system in disarray even eight months after first testing positive. The body’s cells do not appear to recover.
Images of micro clots as seen under an electron microscope. PHOTO: Supplied
The third, an area in which Pretorius has distinguished herself internationally, is that COVID-19 is not only a lung disease but significantly affects the vascular (blood flow) and coagulation (blood clotting) systems of the body.
A recent study published in the Cardiovascular Diabetology journal, conducted by Pretorius and colleagues, found that there is significant microclot formation in the blood of both acute COVID-19 and long COVID patients. A microclot is a blood clot that can only be seen through a microscope.
Pretorius explains that in a healthy person clots may form, for example, when you cut yourself. The main clotting protein is a molecule called fibrinogen. “When you’re healthy, it’s in solution. And then when you cut yourself, collagen is exposed, and a little gel called fibrin prevents you from bleeding out. In healthy individuals, the clots are then broken down by a process called fibrinolysis.
Blood samples from patients with long COVID have revealed high levels of various inflammatory molecules trapped in the microclots including fibrinogen and Alpha-2 antiplasmin – a molecule that prevents the breakdown of microclots.
The persistent blood clots essentially result in cells not getting enough oxygen in the tissues to sustain bodily functions. This, Pretorius says, may be central to numerous debilitating symptoms.
In healthy individuals, the body’s plasmin-antiplasmin system maintains a fine balance between blood clotting to prevent blood loss after an injury and fibrinolysis which prevents blood clots from forming.
With high levels of alpha(2)-antiplasmin in the blood of acute COVID-19 patients and individuals suffering from long COVID, the body’s ability to break down the clots is significantly undermined. The blood circulation becomes clogged up.
Microclots are generally not found in people who do not have long COVID. Pretorius says you can find them in some other conditions, such as diabetes, “but the difference is the number and the extreme presence of the clots with long COVID, that’s what’s making the difference,” she says.
Insoluble clots
Another difference is that the clots in long COVID are insoluble. When Pretorius tried to dissolve these clots using an enzyme called trypsin in her laboratory, they would not dissolve. They are resistant to fibrinolysis.
Initially, Pretorius was looking at acute COVID-19 infection. We received blood samples from ICU patients and we made blood smears and looked at them under a scanning electron microscope that can enlarge a sample hundreds of thousands of times. We then added a fluorescent dye or marker called Thioflavin T which lights up when there are misfolded proteins. This happens when, for example, the spike protein binds to the soluble fibrinogen molecule making it insoluble.
The SARS-CoV-2 virus is known to bind to ACE2 receptors and TMPRSS receptors which are found on platelets (blood cells that help with clotting). They are also found on the endothelium (the inner-most lining of the blood vessels). By binding to the platelets and the endothelium, the virus sets off a torrent of clotting causing vascular damage.
Pretorius says in early 2021, “I got a report from Harvard collaborators and others to say that patients do not fully recover post-infection and they referred to this as long COVID.
“I said let’s get the samples. We looked at the blood samples and lo and behold we found the clots and they were fully persistent. I was not surprised to find the clots in long COVID because I knew with acute COVID many people were dying because of clots in the lungs and shortness of breath. But, I did not know the extent to which they were present in long COVID.”
“When we did proteomics analysis on the sample, when we looked at the different molecules in the blood, I could not dissolve the sample with typical enzymes. I used a massively abrasive enzyme called Trypsin which dissolves any possible protein. But it could not dissolve these cells. The resilience of these clots, that they simply don’t get dissolved, surprised me,” Pretorius says.
Pretorius recalls that in 2020, several South African clinicians alerted others to COVID-19 not being a typical viral pneumonia but suggested it was also a vascular disease. “At that stage, it was massively controversial with many dismissing this idea saying it’s a virus that affects the lungs and that’s it,” she says.
Pretorius says this was despite papers published overseas in 2020 that concluded COVID-19 was also a vascular disease. “It was made controversial in South Africa but it is now widely accepted that COVID-19 also affects clotting as well as the body’s vasculature (network of blood vessels).”
Pretorius says, “Although the microclot is a theory, it encompasses all of the other suggested causes of long COVID because the spike protein itself can trigger microclots. We have submitted a paper, looking at many more blood samples, where we found inflammatory molecules trapped inside the blood clots which do not break down. We also found antibodies so the theories about immune abnormalities, persistent virus, and microclots are intertwined. All of these can cause organ damage. So if you look at it from a systems biology approach, all of these are valid.”
Many are told that their symptoms are possibly psychological, all in their head, and they are told to get some rest and to stop stressing. Meanwhile, the patients are very ill
Diagnostics
Pretorius says there are no general pathology tests readily available to diagnose people with long COVID.
“People that are desperately ill – bedridden or in wheelchairs – are often given generalised blood tests. They are told that their pathology test results are within normal to healthy ranges. Many are told that their symptoms are possibly psychological, all in their head, and they are told to get some rest and to stop stressing. Meanwhile, the patients are very ill,” she says.
Pretorius says the main reason the traditional laboratory tests do not pick up any of the inflammatory molecules is that they are trapped inside the insoluble microclots. A typical pathology test looks at the soluble content of the blood, so if the molecules are trapped they will be missed.
“We patented a long COVID test which is just a simple microscopy test that is a useable diagnostic method to see if microclots are present,” Pretorius says.
Microscopy methods are not readily available at pathology laboratories. However, Pretorius says, “We have crowd-funded and received funding from the Polybio Research Foundation in America to buy a flow cytometer for our blood lab to develop a flow cytometry method that can be used in the typical pathology labs. So we hope to have a diagnostic that will be readily available in a couple of months.”
Treatment
Pretorius says colleagues in the United Kingdom have already designed two randomised controlled trials to independently test both coagulation therapy (CLOTT-UK) and Apheresis (CLOTT-Apheresis trial ) in which microclots and inflammatory molecules are filtered out in a dialysis-type treatment. These trials will study whether anticoagulants and Apheresis give long-lasting relief of symptoms. These trials are being planned and researchers are waiting for ethics approval.
In addition, colleagues from the University of Sheffield Hallam and from the University of Manchester have independently set up microclot testing in their labs and they are planning to publish their UK cohort results soon. They are also correlating long COVID severity to microclot presence, says Pretorius.
“It’s been quite a ride. Seeing the devastation of long COVID, I realise why I decided not to be a clinician… handling and hearing all the issues is just so sad,” says Pretorius.
But, she remains determined to help “crack” long COVID.
Vaccination only reduces the risk of long COVID after infection by only about 15%, according to a study of more than 13 million people published in Nature Medicine. That’s the largest cohort that has yet been used to examine how much vaccines protect against the condition, but it is unlikely to end the uncertainty as other studies have produced conflicting results.
Studying long COVID has been challenging not least because of how hard it is to define from its constellation of symptoms. Even its prevalence has been hard to determine, with some studies suggesting it occurs in 30% of people after COVID infections. But nephrologist Ziyad Al-Aly and colleagues conducted a study of about 4.5 million people treated at US Department of Veterans Affairs (VA) hospitals, and the findings suggested that the number is 7% overall and lower than that for those who were not hospitalised.
Another mystery has been whether long COVID is less likely to occur after a breakthrough infection. But Al-Aly’s team now looked at VA health records from January to December 2021, including those of about 34 000 vaccinated people who had breakthrough SARS-CoV-2 infections, 113 000 people who had been infected but not vaccinated and more than 13 million people who had not been infected.
These results indicated only 15% a reduction of Long COVID in vaccinated individuals, a marked contrast to previous, smaller studies which suggested much higher protection rates. It’s also a departure from another large study, which used self-reported data from 1.2 million UK smartphone users and found that vaccination halved the risk of long COVID.
The authors of the latest study also compared symptoms such as brain fog and fatigue in vaccinated and unvaccinated people for up to six months after they tested positive for SARS-CoV-2. The team found no difference in type or severity of symptoms between those who had been vaccinated and those who had not. “Those same fingerprints we see in people who have breakthrough infections,” Al-Aly said.
In the US alone there have been over 83 million COVID infections, he noted. If even a small percentage of those turn into long COVID, “that’s a staggeringly high number of people affected by a disease that remains mysterious”.
Such limited protection means putting vulnerable people such as the immunocompromised at risk if measures such as masking are withdrawn. “We’re literally solely reliant, now almost exclusively, on the vaccine to protect us and to protect the public,” said Al-Aly. “Now we’re saying it’s only going to protect you 15%. You remain vulnerable, and extraordinarily so.”
“Generally speaking, this is horrifying,” said David Putrino, a physical therapist at Mount Sinai Health System in New York City who studies long COVID. While he praises the study, he notes that it is limited because it does not break the data down by key factors, such as medical history. “These are very important questions we need answers to,” Putrino says. “We don’t have any really well constructed studies just yet.”
Steven Deeks, an HIV researcher at the University of California, San Francisco, points out that the study includes no data from people infected during the period when the Omicron variant was causing the majority of infections. “We have no data on whether Omicron causes long COVID,” he says. The findings, he adds, “apply to a pandemic that has changed dramatically”.
Deeks added, that the results do highlight the need for more research on long COVID, and for accelerated development of therapies. “We don’t have a definition, we don’t have a biomarker, we don’t have an imaging test, a mechanism or a treatment,” he said. “We just have questions.”
