More than two years of long COVID research hasn’t yielded many answers: scientific review

The world has been grappling with the spectre of long COVID since mid-2020, when some patients realized their COVID-19 symptoms hadn’t fully disappeared — but nearly three years later, how much do we really know about this persistent issue?

A new paper reviewing the existing studies on long COVID is suggesting that research is still sorely lacking in providing relief for patients, and that clinicians and researchers need to learn more about a chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), in order to truly understand and treat long COVID.

Published Friday in the peer-reviewed journal Nature Reviews Microbiology, the review aims to condense the body of research surrounding this complicated condition in order to paint the most detailed picture yet of an illness authors say is impacting, in some form, at least one in ten people who have contracted COVID-19.

Around 65 million individuals are estimated to have experienced long COVID, the review states. The baseline definition of long COVID, also known as post acute COVID-19 syndrome, is a person experiencing persistent symptoms for at least three months after their acute COVID-19 infection has cleared up.

“On the basis of more than two years of research on long COVID and decades of research on conditions such as ME/CFS, a significant proportion of individuals with long COVID may have lifelong disabilities if no action is taken,” the authors wrote.

Among the review’s key findings are that while the presentation of long COVID can vary drastically, it’s clear that there are biological impacts to multiple organs and systems, and that long COVID has significant overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia, a blanket term for a variety of conditions relating to the malfunctioning of nerves controlling involuntary functions like blood pressure, heart rate and sweating.

Some of the most common symptoms seen in long COVID patients, such as brain fog and extreme fatigue, are also seen in patients with ME/CFS.

Due to the high prevalence of ME/CFS, a type of dysautonomia relating to heart rate called POTS, and “other postinfectious illnesses in patients with long COVID, long COVID research should include people who developed ME/CFS and other postinfectious illnesses from a trigger other than SARS-CoV-2 in comparator groups to improve understanding of the onset and pathophysiology of these illnesses,” the review stated.

But while long COVID could be a matter of months for some patients, for others, long COVID has had debilitating impacts, with symptoms persisting for greater than a year and changing their quality of life dramatically.

Food having zero taste for over a year, previously benign smells producing instant nausea, a persistent ringing sound in the ears, and fatigue so debilitating it requires a wheelchair and permanent disability leave — these are just some of the symptoms of long COVID that dozens of Canadians have described to

“Most days I can’t leave my house, I’m so dizzy … I can’t even stand in the shower anymore,” Nicole Rogers told last week.

Read more: Long COVID a ‘whole-body disease,’ with some patients experiencing loss of taste and smell for months: expert

According to this new scientific review, we’re making progress towards understanding the condition, but much more needs to done.

There is also a lack of clarity about the incidence of long COVID and the impact of vaccination, variants and reinfections due to “differing study methods, time since vaccination and definitions of long COVID,” the study authors state.

The review found that the incidence level had a wide margin, estimated at 10-30 per cent of non-hospitalized cases, 50-70 per cent of hospitalized cases and 10-12 per cent of vaccinated cases. However, it’s still unclear what the incidence of severe cases of long COVID is —meaning those with symptoms measured in years rather than months.

How long COVID impacts the body

Long COVID can have impacts in the heart, lungs, immune system, pancreas, gastrointestinal tract, neurological system, kidneys, blood vessels and reproductive system, the review found.

These biological systems were laid out in a figure with their associated long COVID symptoms and what the pathology — or the cause — behind these symptoms might be.

The overlapping nature of the pathology behind symptoms can make it harder to manage or diagnose the issue, the review noted.

For instance, one of the main symptoms of long COVID is persistent fatigue. The review listed numerous pathologies that could be contributing to this, including tiny blood clots, pulmonary embolisms, strokes, and microangiopathy, which refers to issues with the structure of small blood vessels.

Researchers still haven’t pinned down the cause of long COVID, and “there are likely multiple, potentially overlapping, causes,” the review stated.

Across the studies reviewed, numerous theories have been suggested. One is that there are persisting reservoirs of the virus leftover in tissues, while another suggests the virus reactivates underlying conditions or pathogens in certain patients.

Another theory is that long COVID is caused by immune dysregulation, which is when the body can’t rein in its own immune response. Immune dysregulation often plays a role in autoimmune conditions, wherein the immune system attacks the body’s cells.

Blood clotting and dysfunctional signalling from the brainstem throughout the rest of the body are two other prominent theories, the review noted.

Researchers also still don’t know much about why some people get long COVID after an acute COVID-19 infection and others don’t.

But the review found some patterns emerging — patients who developed low or no antibodies against SARS-CoV-2 during their acute infection were more likely to have long COVID at six to seven months after testing position for COVID-19.

Viral persistence of SARS-CoV-2 within the body also is correlated with long COVID across several studies.

Lack of knowledge hampering patient care

In research surrounding long COVID, one term that comes up a lot is ME/CFS. This multisystem illness usually appears after a viral or bacterial infection, and is characterized by severe fatigue that causes a substantial reduction in their ability to participate in daily social and occupational activities, as well as a huge increase in negative symptoms directly following exercise, called postexertional malaise.

The fatigue experienced by those with ME/CFS can be extreme — most patients are unable to work, according to the review.

“Many researchers have commented on the similarity between ME/CFS and long COVID; around half of individuals with long COVID are estimated to meet the criteria for ME/CFS, and in studies where the cardinal ME/CFS symptom of postexertional malaise is measured, a majority of individuals with long COVID report experiencing postexertional malaise,” the authors wrote.

Another issuing surfacing in long COVID patients is dysautonomia, which is frequently comorbid with ME/CFS, particularly a type of dysautonomia called POTS, in which a person heart rate abnormally spikes after sitting up or standing.

However, ME/CFS isn’t well known within the general population or the medical population, according to the review, meaning that diagnostic and treatment lessens specialists have learned with ME/CFS are often not being applied to long COVID patients. Only six per cent of U.S. medical schools fully cover ME/CFS in terms of treatment, research and curricula, according to the review.

Dysautonomia is also often misdiagnosed as psychiatric or psychological disorders due to its symptoms presenting as similar to mental health issues such as anxiety.

Often ME/CFS is left out of health record data because general practitioners are unaware of it, leading to holes in the data record.

“Because ME/CFS and dysautonomia research is not widely known or comprehensively taught in medical schools, long COVID research is often not built on past findings, and tends to repeat old hypotheses,” the review stated.

This lack of awareness can lead to patients being unaware of how to manage their long COVID. While some clinicians treating long COVID patients utilize physiotherapy, exercise can make things worse for those with symptoms similar to ME/CFS, according to the review.

“Of note, exercise is harmful for patients with long COVID who have ME/CFS or postexertional malaise, and should not be used as a treatment; one study of people with long COVID noted that physical activity worsened the condition of 75 per cent of patients, and less than one per cent saw improvement,” the review stated.

Sparse effective treatment options

There are “no broadly effective treatments for long COVID” at present, according to the review.

Some strategies have helped to address patients experiencing certain specific symptoms. For instance, strategies that are applied to ME/CFS patients have shown effectiveness with long COVID patients experiencing similar symptoms. Patients with blood clotting issues are usually given anticoagulant regimens, which thin the blood to prevent it from clotting.

While there have been pilot studies into the effectiveness of certain drugs or medical treatments, there is a clear need for clinical trials, and funding for those trials, in order to assess if these options can be offered to patients more widely, the review found.

Research is still lacking

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There have been numerous studies investigating the impacts of and causes behind long COVID, as well as numerous diagnostic and treatment options being developed, but there are still huge gaps in our knowledge, according to the review.

Inconsistent testing for COVID-19 is a problem in terms of diagnosing long COVID, authors noted, adding that some long COVID clinics require a record of a PCR test for admission. Other clinicians and researchers decide who does or does not have long COVID based purely on the presence of antibodies indicating a previous COVID-19 infection, even though around 22-36 per cent of those who contract COVID-19 don’t produce antibodies as a result, according to the review.

This and other factors such as discounting lesser-known symptoms such as postexertional malaise can skew research, authors wrote.

Moving forward, research needs to cast a wider net in terms of symptoms and incorporate experts in postviral illnesses such as ME/CFS, the review recommended.

“Although research into long COVID has been expansive and has accelerated, the existing research is not enough to improve outcomes for people with long COVID,” the authors stated.

“Because ME/CFS and dysautonomia research is not widely known across the biomedical field, long COVID research should be led by experts from these areas to build on existing research and create new diagnostic and imaging tools.”

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