Health organisations across the world are rushing to prepare for a wave of debilitating post-Covid-19 illness that we know little about.
Photo: Vinay Ranchhod
Research in New Zealand into the post-viral condition known as Long Covid is now being carried out.
It is building on key insights from studies of another disease - Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - once maligned and often still neglected by the medical establishment.
ME/CFS has striking similarities to Long Covid in terms of symptoms and the demographic it affects.
Some experts are postulating Long Covid could be a sub-type of ME/CFS.
Those leading research into Long Covid here are looking to see if this is the case, while probing for a possible intervention to arrest the course of the disease.
So, could Long Covid be ME/CFS by another name and what could you expect to experience if you developed this type of post-viral disease?
Here's what you need to know.
The World Health Organisation (WHO) says one in four people will have symptoms a month from the onset of SARS CoV-2, and that one in 10 will be left with symptoms for more than three months.
The WHO's case definition states the condition "occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually three months from the onset of Covid-19 with symptoms that last for at least two months and cannot be explained by an alternative diagnosis.
Its In the wake of the pandemic - Preparing for Long Covid policy document published this year, states: "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."
The nature of ME/CFS
ME/CFS has blighted the lives of millions across the world for many years, yet relatively little is known about it. There is no one accepted case definition, and little research has been carried out to study and treat it.
Even worse, a theory that the condition was psychosomatic, made popular in medical circles by UK psychiatrist Sir Simon Wessely, left sufferers battling to be taken seriously by doctors.
However, recent research programmes in Japan and those led by Stanford, Harvard and Columbia universities, and the Academy of Medicine in the US, are dismantling the destructive mischaracterisation of it being psychological illness.
In New Zealand, University of Otago's Emeritus Professor Warren Tate's work has also helped comprehensively reframe ME/CFS as a complex biomedical illness that involves an immune system dysfunction.
Research by Tate, and then together with Associate Professor Aniruddha Chatterjee published in the Journal of Translational Medicine and Clinical Epigenetics, unequivocally pointed to the illness being in the physiology of the sufferers, and not in their heads.
Looking at molecular studies, they mapped key changes in important physiological and biochemical pathways and systems in ME/CFS sufferers compared with those of healthy people. Tate says the molecular changes help explain the diverse symptoms experienced and the ongoing disease course.
Sufferers' experiences include pain in organs and tissues, brain fog, headaches, fatigue, and disturbances of the autonomic nervous system, which regulates functions like heart rate, blood pressure, sleep, respiration, digestion and bladder control.
Emotional lability and depression are not uncommon, due to the devastating impact the disease has on sufferers' lives.
Tate, a biomedical scientist, is now collaborating with Auckland-based cellular immunologist Dr Anna Brooks to study Long Covid and post-viral illness more comprehensively.
The pair have been awarded funding from separate sources and are working to their own scientific remits.
Tate was awarded funding from Brain Research New Zealand at the end of 2020, initially to compare the molecular signatures discovered in ME/CFS with those in Long Covid.
Brooks used crowdfunding, which included support from The Associated New Zealand ME Society (ANZMES).
Brooks now leads the 'Immunity and Molecular studies of SARS-CoV-2 infection, post-viral conditions, and COVID-19 vaccination' study, launched in October, looking at immune dysfunction and multi-system dysregulation that occurs following Sars-CoV-2 infection and comparing it to those with ME/CFS.
The pair's research may determine whether the two diseases share a common biomarker.
Tate calls Long Covid the 'sister disease' of ME/CFS, sharing core symptoms.
He says the main difference between the two is ME/CFS can be caused by several viruses, including Epstein Barr, and also by non-viral sources like trauma and agricultural chemicals, whereas what we call Long Covid is caused by just one pandemic virus, Sars-CoV-2.
Long Covid also includes unique symptoms particular to the effects of Covid-19, including hypercoagulation, a condition that causes blood to clot more easily.
Individual ME/CFS sufferers may also have unique symptoms relating to the source of their disease.
Professor Warren Tate Photo: RNZ
"I wasn't surprised when the pandemic spun out these ongoing conditions, because it's a classic post-viral disease," he says.
"I mean, the brain fog, the fatigue, the post-exertional malaise, these are the core symptoms of ME/CFS and those are symptoms that people with Long Covid-19 have. The number of symptoms collected and published for Long Covid is as long as your arm, as it is with ME/CFS.
"Each individual person has these core symptoms and might have a few more. But they're kind of individual - it's the individual way in which their immune system has responded to the initial infection."
Tate said a dramatic response of the immune system to Covid-19 disorientates and disrupts it, as with ME/CFS, likely leading to systemic inflammation, including in the brain, and molecular changes in the DNA itself.
He says Long Covid and ME/CFS affect women more than men, who are also more prone to it in middle-age.
"The data is quite clear on that and that came out with the World Health Organisation's definition - that it's mainly a disease of women and it's in the same age group of ME/CFS," he says. "Its profile looks extremely similar to the ME/CFS demographics."
Research history
Tate's interest in Long Covid and 30-year involvement in ME/CFS research goes back to his own family. His daughter has battled ME/CFS from the age of 14, after falling ill in 1990.
"The clinicians didn't have any idea what was going on, even though we'd had our own 'Tapanui flu' a few years earlier in a south Otago town quite close to Dunedin, one of these mysterious outbreaks, which led to ongoing disease," he says.
"The default position, of course, for clinicians world-wide has been if they can't find out what's going on with the disease it is parked in the psychological-psychiatric kind of default position ... UK psychiatrist Simon Wessely had postulated patients 'perceived' their symptoms, perceived they had disabilities and so therefore perceived that everything in life was too difficult for them."
Tate says his experience of having a family member afflicted by ME/CFS made it "quite clear there was a biological basis".
"For a start we knew in my daughter's case it came from a viral infection, as with most people. That it had an organic cause. Even the psychiatrists in Britain acknowledged that - it was initially from an organic cause."
Tate unsuccessfully attempted to get research funding in the 1990s.
"It was another 20 years before I was able start the research ... to show [the] disease has a biological basis," he says.
Tate realised however, the traditional biomedical way of approaching the subject wouldn't be enough. He took inspiration from Stanford geneticist, Michael Snyder, putting together a methodology that would ultimately lead to him to map molecular changes across a wide range of physiological processes when ME/CFS relapses gripped sufferers' bodies.
"Snyder did a very self-focussed study on himself," he says.
"He had blood taken over a two-year period and looked at what was happening to all of the classes of molecules in his body during that time. He was interested in his health profile.
"In those two years all he had was one cold and an upper respiratory infection, RSV ... but the amazing thing is you could see all the molecules changing during even the common cold, and then coming back again to balance.
"I thought 'this was an ideal way in which to study an unexplained disease with a complex pattern of symptoms like ME/CFS'."
Studies have shown how ME/CFS affects various pathways of the body. Similar research is being carried out on Long Covid. Photo: AFP
Snyder's study cost several million dollars. Without having research money from mainstream investment agencies, Tate did a scaled-down study initially, "on the smell of an oily rag". Subsequent funding came from donations from patients' families and the ANZMES.
The study managed to show changes in the immune cells, the energy-producing mitochondria, and in DNA epigenetic code itself in ME/CFS sufferers.
"What we did was study small, well-diagnosed cohorts of patients - 10 patients, 10 age and gender controls, very intensely and I looked at several major classes of molecules. From that, we generated the data and what we found was you can interpret the molecular changes by what is happening with regulation of the expression of the genes in the DNA genome.
"We look at the RNA transcripts made. We looked at 13,000 of those in the patients and the controls and the very careful statistics. With such small patient groups we found there were 33 transcripts that were different and we found the top three, in fact, were involved in inflammation."
Loosening the statistical stringency of the study allowed him to identify more transcripts that were likely affected to see what physiological pathways were changing in ME/CFS sufferers.
It showed their cellular energy production centres - the mitochondria - were out of whack and suggested dangerous levels of oxidative stress were present.
The study then showed a lowered rate of metabolism, something researchers at Stanford University had already picked up.
"A researcher did a study of plasma metabolites, as a measure of the end products of all of our biochemical pathways, and found that many of them were low," Tate says.
"So, he concluded that every body of any ME/CSF person was kind of in a state of hibernation. It was like an animal that was hibernating and hitting a low rate of activity, and he thinks now that's a kind of protective response from an ongoing perception of danger.
"What we showed was the circadian clock, which controls all of the autonomic functions of your body, including sleeping, was affected. That was in the transcripts."
A series of studies showed clear evidence of immune pathway dysfunctions and inflammation, implicating the mitochondria.
"We looked at the immune-cell proteins, 3000 of those, and we showed a hundred proteins were changed in their amounts of immune cells, and interestingly half of them were found in the mitochondria, the energy-production factory of the body."
Tate explains every cell has many mitochondria, delicate sub-structures that are energy-production factories, which produce the chemical ATP - the energy currency of the cells and our body. In ME/CFS sufferers the protein "workers and machines" for making ATP are provided with too great or two small amounts.
To determine why this was happening, his team went back to the DNA genome to see what was happening there.
Tate says they found the DNA's epigenetic code was dysfunctional, sending faulty signals to the body.
"The epigenetic code encompasses tiny sites, flags if you like, right throughout our DNA genome of three billion bases, which act like on-off light switches, or dimmer switches, and they control the expression of information to make just the right amount of proteins for a healthy physiology.
"We have just exactly the right balance amazingly so we can function as healthy human beings. And so, we wanted to go back and see, is this disrupted in ME/CFS patients, so that way, we know they're not producing things in such a delicate balance, like in a healthy individual. And we certainly have found that.
"We found lots of individual sites with changes on the DNA, across the three billion bases, and we could link those specific genes and specific pathways. And again, we came up with many of the same pathways we've seen in the early analyses.
"And so we could see that's the molecular site where all the dysfunctional physiology starts really, because the information flow is not flowing totally correctly. Now, what causes that? Why is this affected at the DNA level? That isn't totally clear."
He suspects neuro-inflammation is playing a high-level role in the disease, possibly affecting how parts of the brain centres work and in turn triggering the profoundly disturbed biological response and the correlating symptoms afflicting ME/CFS sufferers.
ME/CFS global movement #MillionsMissing campaigners outside the Irish Parliament demand increased government funding for research, clinical trials and medical education. Photo: AFP
"For example, the stress centre within the hypothalamus, and the hypothalamus pituitary adrenal axis, which leads to hormone production - all of that is affected," he says.
"There has been one Japanese study that showed evidence of neuro-inflammation that was directly in proportion to the severity of the ME and showed there were activated microglia in the brain. That's a marker of neuro-inflammation.
"We published a model of neuro-inflammation in the hypothalamus, and there are all sorts of subsequent consequences of that, in terms of production of stress hormones. In fact, that stress hormones resulting in production excessive serotonin and lowered cortisol. So, there's a whole cascade of things that can occur."
Long Covid study
Tate and Brooks are now carrying out a broader studies, looking for the same cellular immunity disturbances in Long Covid patients.
"For my part, it's just moving from what we found within ME/CFS - these molecular signatures, if you like, and the energy-production system, and all the DNA and the epigenetic code - seeing if those signatures are there with Long Covid," Tate says.
An aspect of their study involves seeing what changes take place when Covid Long-haulers and ME/CFS sufferers are vaccinated.
Some have postulated the Pfizer jab may "kickstart" or reset the immune system in Long Covid patients, addressing their dysfunctional physiology, but anecdotal evidence also suggested improvement was not permanent, he says.
Most reports had been negative. A significant number of those with ME/CFS have had severe relapses of their illness triggered by the vaccine, Tate says.
According to his data, there have been ME/CFS sufferers infected with Covid-19 who experienced a worsening of their long-term symptoms, while Long Coviders had subsequently been diagnosed with ME/CFS by doctors due to the extremity of their conditions.
He acknowledged limitations when comparing the ME/CFS and Long Covid sufferers. Long Covid haulers in New Zealand have had their disease for maybe only a year, whereas many ME/CFS sufferers had been ill for decades.
What isn't clear is whether Long Covid will be a life-long disease like ME/CFS. If Long Covid is found to be a sub-type of ME/CFS, the chances are it will follow similar disease patterns.
Tate says 95 percent of ME/CFS patients never recover normal health and that figure may be higher, due to misdiagnosis and people merely adapting to the condition over a long period of slow improvement and forgetting what it is like to feel normal.
"Those that haven't moved out of the acute phase tend to be housebound, sometimes even bed-bound. And some of these gradually get worse and end up confined to darkened rooms, unable to tolerate sensory stimulus."
There is hope though.
When studying the relapse-recovery cycles of individual ME/CFS patients, Tate found specific sites in the DNA changed the epigenetic code and then the code reverted back to normal when the sufferer recovered. He said the changes correlated to a worsening of the ME/CFS dysfunction and inflammatory pathways of the body and then a recovery to normal functioning without symptoms.
This reversal pattern offered reassurance the disease path wasn't necessarily progressive and permanent like other types of neurological disease.
The answer could be found in "convincing the body that it's not in danger, so it doesn't have to keep putting out signals all of the time and shutting things down, and then allowing the body to heal," he says.
"I think we're on the verge of finding something to make the switch."
Tate says Brooks' contribution to the research has added new layers.
"Anna and I started talking because Anna is a specialist studying the immune cells, the cellular immunity, and she has a lot of techniques and skills and equipment to do that and are skills were complementary.
"For me that was exciting because we could expand then the whole thing of connecting molecular changes to what's going on within the immune system at the cellular level."
Biomarker for Long Covid
Brooks says there are about 150 participants in the study she leads since it launched in October and numbers are increasing weekly.
All those taking part have post-viral illness and don't need to prove they've had Covid-19. Not everyone had access to a PCR test in 2020 and some people don't create antibodies to the virus, she points out.
Dr Anna Brooks Photo: Supplied/Anna Brooks
"Anyone with a post-viral condition that was triggered since early 2020 is most welcome on our study because everyone matters, and if we found out that if it was triggered by Covid then we feed that back and if it's not, you're still in our study too," she says.
The study is inclusive and offers post-viral illness equity. It is based on the supposition 'Long Covid' isn't a new syndrome.
"It's not. That's not that to say there's going to be unique features and it could be this virus triggers more ME than any other virus," she says.
"That could be the unique feature. But essentially the key feature of our research is that every post-viral condition matters."
She says a number of hypotheses about Long Covid are in play internationally, including "viral debris".
"We do believe there's been an inflammatory disruption in people with Long Covid because essentially what we're seeing reported is that there's been a poor immune response, so that could mean as the immune system is clearing away and shutting down the viral infection, it's not doing it to it's full capacity and it's left something behind. However, there's many layers to the disruption that likely goes beyond the immune system."
Brooks is also involved in research looking at a hypothesis that micro clots are implicated in the cause. She is currently working alongside an international group of scientists testing the theory.
It came out of research by Professor Resia Pretorius, at the Department of Physiological Science at Stellenbosch University (SU) in South Africa, who studied micro clots and their molecular content in blood samples of Long Covid patients.
Her peer-reviewed findings, published in the Journal Cardiovascular Diabetology in August, indicated an overload of various inflammatory molecules, "trapped" inside insoluble microscopic blood clots, might be the cause of some symptoms.
"It's a possible biological mechanism for what's happening," Brooks says.
Post-viral illness now in spotlight
The medical establishment remains a somewhat cold house for those battling to put post-viral illness on the agenda.
That's reflected from conversations Brooks has had with some of those in the study.
"It's just so disheartening the amount of emails I get from participants who say, 'how soon is it you're going to prove I have Covid because I need to prove it to my doctor'," she says.
"It just baffles me because I'm like, 'why do you need proof of this thing that infected you for you doctor to take you seriously when you've described all these symptoms?'"
ME/CFS support groups there for Long Covid sufferers
A Facebook Long Covid support group in New Zealand of over 200 members reflects increasing numbers with the disease.
Existing ME/CFS support groups in New Zealand are also in a position to offer immediate assistance too, although lack of funding limits the number they can help.
Vice-president of ME Auckland, Kate Duder Photo: Supplied/Kate Duder
"Our supports systems are a little stretched at the moment," ME Auckland vice-president Kate Duder says.
"As a non-profit organisation we're trying to secure more funding to be able to take on another client support co-ordinator to increase capacity, but we won't turn Long-Covid people down when they come to us."
Duder says, while Covid symptoms are largely similar to those of ME/CFS, another common experience has been the dismissive scepticism of some clinicians.
"We've realised we're in a unique position to support people in Auckland with Long Covid, because we know how to help people with ME and a lot of the doctors don't and from what I've heard a lot of the doctors are actually gaslighting Long Coviders as well and don't know how to deal with their symptoms," she says.
'Huge burden on health system'
Tate says it is now incumbent on the Ministry of Health to fund post-viral illness support and research.
"I'm of course expressing a bias here, but these diseases are going to be a huge burden on the health system, on families, on the community. I think funding should be a given with the same priority as with Alzheimer's disease. The number of people with Alzheimer's probably about 50,000 now, only about twice as many as a ME, but there is a huge funding gulf."
There is greater recognition of this internationally now with the emergence of Long Covid. The National Institutes of Health in the US has allocated $1.15 billion dollars towards Long Covid-19 research as the case numbers continue to rise in the United States and worldwide.
"It's hoped that the ME/CFS community will be part of and benefit from that research," Tate says.
A Department of Health spokesperson says it has commissioned a major piece of longitudinal research of people that had contracted Covid-19 in Aotearoa.
"Te Herenga Waka-Victoria University of Wellington has been awarded the contract for this research and is currently in the final stages of preparation, with participant recruitment likely to start soon."
The Ministry statement adds: "The study will look at the impacts of Covid-19 over time, with a specific focus on the health and wellbeing of Māori, Pasifika, those living with a disability, and those who were infected through their workplaces. The experiences of those with Long Covid will also be included.
"We have also issued rehabilitation guidance for acute Covid-19 and are looking to update this to take into account Long Covid. We have completed a comprehensive literature review on the topic and are aiming to engage an expert advisory group to translate this into guidance."
