Experts question research suggesting long COVID symptoms may depend on variant

While new research suggests that symptoms linked to long COVID could vary depending on which COVID-19 variant a person is infected with, infectious disease experts say they are not completely convinced this is the case.

The data is based on a study involving 428 long COVID patients treated at a post-COVID outpatient service between March 2020 and June 2021, while the original strain of SARS-CoV-2 and the Alpha variant were both in circulation. It suggests that those who contracted the Alpha variant encountered different neurological and emotional symptoms when compared with those who were infected with the original strain of SARS-CoV-2.

When the Alpha variant was the dominant strain, there were more instances of muscle aches and pains, insomnia, brain fog, and anxiety and depression among long COVID patients. Meanwhile, symptoms such as the loss of smell, difficulty swallowing and impaired hearing were less common.

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However, infectious disease experts question the accuracy of the study, and point to difficulties in assigning specific long COVID symptoms to different variants.

Dr. Christopher Carlsten is the head of respiratory medicine at the University of British Columbia. While he said he commends any effort to better understand COVID-19, he is not yet convinced that the Alpha variant results in a worse COVID-related syndrome than other variants.

“It's a retrospective observational study, which always raises questions of bias in terms of whether [this] is actually truly due to the Alpha variant, or is it due to some other factors that went along with the Alpha variant,” he told CTVNews.ca in a phone interview on March 30. “There's so many variables changing in parallel that to pinpoint any one of those and claim that variable as the cause of some pattern is hazardous.”

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The study was published in an early news release ahead of the European Congress of Clinical Microbiology and Infectious Diseases conference, which will take place later this month.

Looking at the study’s design, it also appears as though researchers did not confirm which variant of the virus caused infection in which patients, said Dr. Nazeem Muhajarine, an epidemiologist at the University of Saskatchewan. Instead, patients were assessed based on whether they were infected when the original strain dominated, or while the Alpha variant was dominant. This raises doubts around the accuracy of the study, Muhajarine said.

“That's a big limitation,” he told CTVNews.ca on March 30 in a phone interview. “You really don't know unless you actually take a specimen and you do that genomic sequencing and find out [whether] this person was infected with Alpha [or] the original virus.

“I'm a little bit unconvinced that specific lingering symptoms can be associated with a specific variant of SARS-CoV-2.”

However, Muhajarine said this remains a key area of interest among COVID-19 researchers and that larger-scale studies will be necessary to get a clearer picture of the causes and effects of long COVID. The authors of the study also state that more research is necessary to better understand long COVID, as much still remains unknown about the condition.

WHAT DO WE KNOW ABOUT LONG COVID SO FAR?

Long COVID, otherwise known as post-acute sequelae of COVID-19 (PASC), occurs when symptoms of an initial COVID-19 infection persist for longer than about 12 weeks after infection, said Muhajarine. At this point, experts would generally expect symptoms to have cleared. As a result, someone with long COVID would not necessarily test positive for the virus while using a PCR or rapid antigen test, Carlsten said.

“When that symptomatology persists beyond the infection, meaning the bug is no longer active to the extent that we can measure it and you continue to have symptoms…that's what I would consider long COVID,” said Carlsten.

As described in the study, long COVID has been diagnosed in both young and old patients, as well as those generally considered healthy and those with underlying health conditions. A recent study suggests that as much as about 30 per cent of those infected with COVID-19 will go on to develop long-term symptoms. However, the exact percentage is still unclear as population-level studies assessing the prevalence of long COVID have not yet surfaced, said Muhajarine.

Still, the condition is real and has the potential to affect a significant number of people, Carlsten said.

“Even modest percentages of patients with COVID having long-term symptoms is a lot of people,” he said. “Rather than obsessing too much at this point about the exact percentage, it's pretty clear that it's a non-trivial percentage and that at a population level, that means lots of people.”

With the recent emergence of Omicron, the idea of long COVID developing in those infected with the latest variant of concern is a possibility, Carlsten said.

“The basic answer is yes – to me, there's no question that Omicron can result in long COVID,” said Carlsten. “I think the question is how much and there I have the opposite answer, which is that I don't know, and I don't know that anyone can tell you at this point.”

Given that the world has only known about the Omicron variant for a few months, Muhajarine said more time is needed to determine the connection between Omicron and long COVID, as well as whether a different set of long COVID symptoms may be attached to this variant when compared to previous ones.

“We are just at that threshold in terms of whether Omicron leads to long COVID, and if it leads to more long COVID compared to the previous variants,” he said. “I think we have to give it some more weeks and months to really be able to say that because I think we are really at the cusp of even that definition of what is long COVID.”

According to Carlsten, the concept of different symptoms being linked to different COVID-19 variants is not a new one. This is due to slight differences in the amount and types of mutations held by each variant, which can trigger different symptoms to appear once a person is infected, said Muhajarine. However, these differences are not usually striking, Carlsten said.

“Over the course of the pandemic, there seems to be more similarities in the symptomatology related to COVID than differences by strain,” he said.

GENERALIZED SYMPTOMS A HURDLE FOR DIAGNOSIS

Commonly reported symptoms of long COVID are shortness of breath, chronic fatigue, trouble sleeping, visual problems and brain fog. A spiking heart rate also appears to be linked to long COVID. One international study suggests as many as 203 symptoms could be connected to long COVID, the most common being fatigue, exhaustion and cognitive dysfunction.

One of the challenges around understanding the cause of long COVID lies in the fact that many of the symptoms associated with it are rather generalized, Carlsten said.

“The fundamental vexing nature of long COVID is that there's not a single symptom that is specific or even remotely specific,” he said. “They're almost, by definition, symptoms that are very common to other illnesses and other medical problems.”

This also makes the condition exceedingly difficult to diagnose and treat, said Carlsten.

“The fundamentals of a diagnosis are that the more specific the characteristics, the easier it is to diagnose,” said Carlsten. “But because these are non-specific … it makes diagnosis more difficult, and treatment accordingly is difficult.”

There isn’t a single test used to diagnose long COVID, Muhajarine said, although certain tests can be used to identify common symptoms, including blood tests, heart rate and blood pressure checks, electrocardiograms and chest X-rays. It does not appear as though there is a single treatment or medication for long COVID either, he said, although experts have begun to try to tackle this question. So far, the focus appears to be on treating some of the symptoms linked to long COVID rather than the condition itself, Muhajarine said, which can involve patient rehabilitation to help with breathing and lung function, for example.

The National Institute for Health and Care Excellence in the United Kingdom, which provides national guidance to improve health care, has put forward a proposal for the management and treatment of long COVID that involves a tiered approach. This begins with patient-led rehabilitation based on self-care, and evolves into recovery guided by a general practitioner or specialist, depending on the severity of the condition. Muhajarine said he can see this being an effective approach to the management of long COVID in Canadian patients as well.

‘AT THE STARTING GATE’ OF MANAGING LONG COVID

As restrictions continue to lift across parts of Canada, this might give people the idea that COVID-19 is in the past, but that is not the case Muhajarine said, especially when looking at the possibility of developing long COVID. As a result, Carlsten said, it is important to continue with efforts to better understand the condition.

“It's a huge issue that we need to continue to try to understand,” said Carlsten. “I think we should persist in the research in spite of the fact that it hasn't, in terms of long COVID, been incredibly revealing, because it is a massive population-level problem.”

Muhajarine also calls on health-care systems to open more clinical facilities that specialize in outpatient treatment for long COVID patients. Provinces such as Ontario and British Columbia have long COVID clinics in operation, but provinces such as Saskatchewan do not, Muhajarine said.

“We are still really at the starting gate of dealing with long COVID in this country, unfortunately,” he said. “We hear stories from people who are experiencing long COVID symptoms and they just feel that they are left high and dry to deal with this on their own.

“This is the legacy that acute COVID-19 is going to leave us with, and this is why we cannot take COVID-19 lightly.”

Muhajarine is also calling on public health systems to build patient registries among those experiencing long COVID. By collecting data on these patients, including their medical history and details of previous infections, this can help better identify patterns that could be used to diagnose the condition more easily, he said.

“First of all, we can identify who is having these symptoms and … secondly, we can monitor them,” said Muhajarine. “We can understand who they are, where they live, what was their history like with COVID-19, and what kind of services are utilizing.

“If long COVID is this big canvas that we need to paint, many places in Canada, including my own province, hardly have a dot of paint on the canvas.”

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