14 Mar, 2022
Exploring Long COVID: March 2022
We share a monthly summary of the latest Long COVID research and findings.
Hello and welcome to your Long COVID research roundup. It’s hard to believe that two years have passed since the coronavirus pandemic first stopped us in our tracks.
Dealing with every aspect of the pandemic has thrown up new challenges and Long COVID has been part of this learning curve. First highlighted by patient advocates in the early months of 2020, Long COVID - the term given to clusters of ongoing symptoms following COVID-19 infection - has remained steadily under the spotlight.
Long haulers have campaigned tirelessly for recognition, research and rehabilitation and, since the first wave of the pandemic, their efforts have certainly gained traction.
Long COVID is widely acknowledged as a multifaceted and often debilitating condition. It has been recognised by the World Health Organisation and several countries, including the United Kingdom and United States, have opened Long COVID clinics. Reassuringly for long haulers, large-scale funded research into Long COVID is actively taking place and our understanding of this complex condition continues to grow.
Living with COVID-19?
A ‘living with COVID-19’ plan was recently announced by the government in England, including phasing-out of free rapid lateral flow tests, reduced access to PCR tests and an end to legal requirements to self-isolate. Other countries have announced similar measures.
Many argue that this approach ignores the risk of Long COVID and leaves those who are immunocompromised in a state of limbo. Referring to the measures, campaign and advocacy group Long COVID SOS commented, “There has now been substantial research to confirm without doubt that this virus leaves a significant proportion of the population with debilitating long term effects - and this includes people of all ages as well as children. Whilst we do acknowledge the importance of a long term economic recovery, we feel strongly that given the current level of infections this should not be at the expense of maintaining wider public health measures.”
For long haulers, there is no option to move on from their symptoms and it’s vitally important that policy makers continue to take Long COVID into account.
This month, we’re revisiting the concept of predicting Long COVID, looking at a new study which reveals four key factors that could help to identify those most at risk. We also highlight recent research showing increased risk of heart complications following COVID-19 infection and two new studies which shed further light on post-COVID smell loss. Let’s find out more…
Who is most likely to develop Long COVID?
Many experts are attempting to answer this question. An early COVID symptom study from King’s College London found that the strongest predictors of Long COVID were increasing age, followed by the number of symptoms in the acute infection phase, hoarseness of voice, greater body mass index, shortness of breath, and being female. People with asthma were also reported to be at greater risk of developing Long COVID.
In last month’s update we drew attention to recent research suggesting that an ‘antibody signature’ could also potentially help to identify those most at risk of developing Long COVID.
Most recently, researchers from the Institute for Systems Biology, the University of Washington and Swedish Medical Centre in Seattle analysed COVID-19 patients and identified four key biological factors that may help to predict the likelihood of Long COVID in the early stages of infection. Their findings were published in the journal Cell.
Researchers focused on a primary group of 209 people, aged 18 to 89, who became infected with COVID-19 during 2020 or early 2021. Seventy-one percent of these participants were hospitalised with the virus. Blood tests and nasal swabs were taken from patients during the acute phase of their COVID infections and two to three months later.
The study also used data from a separate group of 100 patients, many with mild initial infections, from research led by the University of Washington. The results were also compared with data from 457 healthy people.
Researchers analysed participants for 20 Long COVID symptoms and supported their findings with electronic health records. Thirty-seven percent of participants reported three or more Long COVID symptoms two to three months after infection, 24% had one or two symptoms, and 39% said they had no symptoms. Of patients reporting three or more Long COVID symptoms, 95% had one or more of the four key biological factors identified in the study when they were diagnosed with COVID-19.
Four key Long COVID risk factors
The research team discovered that having a higher viral load - measured by the level of coronavirus RNA (ribonucleic acid) in the blood - in the early stages of infection was a key Long COVID risk factor. They suggest that having a higher viral load can make it more difficult for the body to clear the virus.
A second risk factor is the presence of particular autoantibodies - antibodies that mistakenly attack the body’s own tissues. An overreaction of the body’s immune system is also a root cause of autoimmune conditions such as rheumatoid arthritis and lupus.
Another Long COVID risk factor identified by the study is the reactivation of Epstein-Barr virus. Epstein-Barr is a human herpes virus and spreads most commonly through saliva. Many people contract a Epstein-Barr infection when they’re young and the virus then becomes latent in the body. Fourteen percent of participants in the study’s primary cohort experienced a reactivation of their Epstein-Barr virus following COVID-19 infection.
The fourth risk factor was having type 2 diabetes as an underlying condition. Diabetes can weaken the immune system and make people more vulnerable to infections in general. However, researchers note that larger studies may show that type 2 diabetes is only one of several medical conditions that may increase the risk of Long COVID.
This study also uncovered a number of other interesting findings which need further investigation. They found that participants with ongoing respiratory problems had low levels of the stress hormone cortisol, produced by the adrenal gland, and suggested cortisol replacement as a potential Long COVID therapy.
Participants with lingering neurological issues were also found to have elevated levels of proteins associated with disrupted circadian rhythms and sleep/wake cycles in their blood. Study author and president of the Institute for Systems Biology in Seattle Dr Jim Heath told the New York Times that this may provide a way to evidence that patients’ neurological symptoms result from Long COVID.
Early tests and treatments
Study authors accept that the study is limited by several factors, including its relatively small size and the short follow-up period.
However, the team note that their findings reiterate the importance of carrying out early tests on patients following COVID-19 diagnosis. They stress that their study also provides a valuable framework and resource to help fully understand Long COVID and suggest potential strategies, such as anti-viral or anti-inflammatory medications, to treat or even prevent the condition in the early stages of infection.
Long COVID and heart complications
New research published in the journal Nature Medicine has found that COVID-19 infection may increase the risk of developing heart problems for at least one year after testing positive for the virus. These complications can include irregular heart rhythm, blood clots, inflammation, heart attack, and heart failure.
Researchers analysed data from the United States Department of Veterans Affairs (VA) health system from 153,760 people who tested positive for COVID-19 between March 2020 and January 2021. Data was compared to a control group of more than 5.6 million patients who did not have COVID-19 during the same time frame and a control group of more than 5.8 million people who were pre-pandemic patients from March 2018 to January 2019.
What did researchers discover?
Researchers found that participants who had been infected with COVID-19 had significant increases in 20 cardiovascular problems up to one year after infection. Compared to the contemporary control group, people who contracted COVID-19 were 72% more likely to suffer from coronary artery disease, 63% more likely to have a heart attack and 52% more likely to experience a stroke.
Significantly, ongoing heart complications were found to be common even in those who experienced a mild form of COVID-19 and were not hospitalised by the infection. This risk of ongoing heart problems was also observed in participants who were under the age of 65 and with no prior cardiovascular risk factors such as obesity or diabetes. It was also evident in those who had no previous cardiovascular disease before contracting COVID-19.
“Because of the chronic nature of these conditions, they will likely have long-lasting consequences for patients and health systems and also have broad implications on economic productivity and life expectancy,” commented study co-author Dr Ziyad Al-Aly, Director of the Clinical Epidemiology Centre, and Chief of the Research and Education Service at the VA Saint Louis Health Care System.
What causes these heart problems?
Study authors acknowledge that the “mechanisms that underlie the association between COVID-19 and development of cardiovascular diseases in the post-acute phase of the disease are not entirely clear.”
They note that potential causes may include, among others, endothelial cell infection - infection of the cells that line blood vessels and regulate exchange between the bloodstream and surrounding tissue - and the down-regulation of ACE2 - an enzyme attached to the membrane of cells in the heart, kidneys, intestines and other organs - triggered by COVID-19 infection. Experts stress that several mechanisms could be simultaneously at play and further research in this area is needed.
Strengths and limitations
Researchers note the limitations of their study. Veterans are overwhelmingly male and white and the team had to use statistical tools to counter this imbalance. Additionally, those in the contemporary control group had not been tested for COVID-19. This data was also collected before vaccines were widely available and prior to the onset of the virus’ delta and omicron variants.
However, the team also states that their methods are robust, with a sizeable cohort of COVID-19 participants and two large control groups. They note that although prior research has investigated cardiovascular outcomes in the weeks and months following COVID-19 infection, this was mainly focused on hospitalised individuals, with a short follow-up period and a limited selection of cardiovascular outcomes.
Experts recommend that cardiovascular health and disease should be part of post-acute COVID-19 care strategies and stress the need to prevent the virus from the outset via vaccinations.
Overall, there is still much to learn about the impact of COVID-19 on long-term cardiovascular health. Study authors admit that “as the virus continues to mutate and as new variants emerge, as treatment strategies of acute and post-acute COVID-19 evolve and as vaccine uptake improves, it is possible that the epidemiology of cardiovascular manifestations in COVID-19 might also change over time.”
Long COVID and loss of smell: two new studies
Loss of smell and taste has been a key symptom for many people who are infected with COVID-19. For most, this loss of smell, known as anosmia, lasts for weeks or months, but for others the loss persists.
Scientists have already hypothesised about how the virus causes anosmia and have suggested that some COVID-19 sufferers may lose their sense of smell because the virus damages the supporting olfactory cells within their nose that allow olfactory sensory neurons - the neurons that detect smells - to function. Researchers also speculated that infection of these supporting cells might lead to inflammation when the body tries to isolate and combat the virus, which can then impact smell function.
New research, published in the journal Cell, helps to support these theories. A collaboration of scientists from Columbia University and other research centres in California, Texas and New York present a detailed biological explanation for post-COVID anosmia.
The research team used golden hamsters in their study and also examined olfactory tissue from 23 people who had died from COVID-19.
Researchers discovered that COVID-19 viral particles enter the olfactory system in the nasal cavity via supporting cells known as sustentacular (SUS) cells. Commenting on the findings in an interview with Scientific American, study co-author Dr Benjamin tenOever, virologist and director of the NYU Langone Virology Institute, explained, “This cell type performs an important structural role and ensures that related cells, called olfactory sensory neurons, in that tissue are organised in such a way that you can perceive smells.”
He continues, “Following [COVID-19] infection, we find that hamsters have lost more than half of all of their SUS cells in a two-day period. So the structure of the olfactory system has just been totally decayed away because of that significant cell death. And as a result, those SUS cells are now spewing out a great deal of material that triggers inflammation.”
He explains that the adjacent olfactory sensory neurons, which detect odours, are usually occupied with processing smells and making different smell-related receptors, but are instead now focused on reducing the inflammation. Essentially, the way that smells are processed is disrupted by COVID-19.
Dr tenOever adds, “The cells are still there, and the cells aren’t dying. They are just busy doing something else. And so, for a brief period of time, about three to five days after infection with SARS-CoV-2, many people lose their sense of smell.”
Long COVID anosmia and the brain
The research team also acknowledge that for some people, loss of smell can persist for a longer time period and they explore Long COVID and anosmia in a recent preprint study. They suggest that ongoing immune cell reactions in the nasal cavity can travel into the brain and influence emotions and cognition, which could help to explain other Long COVID symptoms such as ‘brain fog’, depression and anxiety.
Researchers carried out experiments on COVID-infected hamsters, both on various organs and parts of the brain. Their analyses found that the entire body carried signatures of inflammation for weeks following viral clearance. However, Dr tenOever commented in the interview with Scientific American, “These changes persisted for a longer time period in the olfactory bulbs, striatum, thalamus and cerebellum. What’s more, those transcriptional signatures show loss of a number of metabolic activities as they maintain this heightened inflammatory state.”
Dr tenOever added that the team also found that hamsters with loss in metabolic activity had performed poorly in behavioural tests which would suggest possible cognitive or behavioural change due to prolonged inflammation. Commenting on the research in Science Daily, he said that “lost sense of smell may act as the "canary in the coalmine," providing any early signals that the COVID-19 virus is damaging brain tissue before other symptoms present, and suggesting new ways to treat it."
Moving towards treatments
Scientists say their next step is looking into whether treating hamsters with Long COVID with steroids can dampen down inflammation and potentially treat post-COVID anosmia and other neurological symptoms.
Dr tenOever explained in the interview with Scientific American that as hospitalised COVID patients are often treated successfully with steroids to reduce inflammation, “This would suggest that the same thing should work in the brain for people with Long COVID, but this needs to first be tested in animals to understand dosage, timing and steroid choice.” Antidepressants will also be explored as a potential treatment.
Significantly, these recent studies both drill down to the root causes of COVID-related anosmia and potentially other neurological symptoms associated with Long COVID.
What do you think?
Have you been living with Long COVID since the first wave of the pandemic? Could you help us understand more about your experience? We’d love to hear your views - please get in touch with our team below.
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