Does long COVID exist?

Long COVID appears to manifest as a post-viral syndrome indistinguishable from seasonal influenza and other respiratory illnesses, with no evidence of increased moderate-to-severe functional limitations a year after infection, according to new research being presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024) in Barcelona, Spain (27-30 April).

The study by Queensland Health researchers suggests that in the highly vaccinated population of Queensland exposed to the Omicron variant [1], long COVID’s impact on the health system is likely to stem from the sheer number of people infected with SARS-CoV-2 within a short period of time, rather than the severity of long COVID symptoms or functional impairment.

The findings add to previous research by the same authors and published in BMJ Public Health which found no difference in ongoing symptoms and functional impairment when COVID-19 was compared with influenza,12 weeks post infection [2].

Rates of long COVID in Australia are low due to high vaccination rates upon easing of COVID restrictions and the population’s subsequent exposure to the Omicron variant. Symptoms reported with the illness include fatigue, brain fog, cough, shortness of breath, change to smell and taste, dizziness, and rapid or irregular heartbeat.

To understand more about the impact of long COVID on the Australian state of Queensland, researchers surveyed 5,112 symptomatic individuals aged 18 years and older, comprising those with PCR-confirmed infection for COVID-19 (2,399 adults) and those who were PCR negative for COVID-19 (2,713 adults: 995 influenza positive and 1,718 PCR negative for both but symptomatic with a respiratory illness) between 29 May and 25 June 2022.

Laboratory reporting for COVID-19 and influenza is mandated upon PCR test request under Queensland’s public health legislation, with the results recorded in the Queensland Department of Health’s Notifiable Conditions System.

A year after their PCR test, in May and June 2023, participants were asked about ongoing symptoms and the degree of functional impairment using a questionnaire delivered by SMS link.

Overall, 16% (834/5,112) of all respondents reported ongoing symptoms a year later, and 3.6% (184) reported moderate-to-severe functional impairment in their activities of daily life.

After controlling for influential factors including age, sex, and First Nation status, the analysis found no evidence that COVID-19 positive adults were more likely to have moderate-to-severe functional limitations a year after their diagnosis than symptomatic adults who were negative for COVID-19 (3.0% vs 4.1%).

Moreover, results were similar when compared with the 995 symptomatic adults who had influenza (3.0% vs 3.4%).

Interestingly, the analysis also found that those who were more likely to report moderate-to-severe functional impairment were those aged 50 years or older, and those who had symptoms of dizziness, muscle pain, shortness of breath, post-exertional malaise, and fatigue.

“In health systems with highly vaccinated populations, long COVID may have appeared to be a distinct and severe illness because of high volumes of COVID-19 cases during the pandemic. However, we found that the rates of ongoing symptoms and functional impairment are indistinguishable from other post-viral illnesses”, says Dr John Gerrard, Queensland’s Chief Health Officer. “These findings underscore the importance of comparing post-COVID-19 outcomes with those following other respiratory infections, and of further research into post-viral syndromes.”

He adds, “Furthermore, we believe it is time to stop using terms like ‘long COVID’. They wrongly imply there is something unique and exceptional about longer term symptoms associated with this virus. This terminology can cause unnecessary fear, and in some cases, hypervigilance to longer symptoms that can impede recovery.”

The authors caution that the findings are associations and do not represent prevalence. They point to several limitations, including that participants who were hospitalised or had pre-existing illness were not identifiable within the cohort. They also note that the risk of long COVID has been lower during the Omicron wave compared with other SARS-CoV-2 variants, and because 90% of people in Queensland were vaccinated when Omicron emerged, the lower severity of long COVID could be due to vaccination and/or the variant.

The paper will be presented at the European Congress of Clinical Microbiology and Infectious Diseases in Barcelona from April 27 to 30.

Expert comment

Ms Marie-Claire Seeley, a PhD Candidate at the University of Adelaide and a Clinical Nurse Consultant, observed that “This abstract reveals a significant finding: approximately 4% of individuals, irrespective of the virus they contracted, may experience persistent health issues post-infection, resulting in chronic incapacitation. This implies that Long COVID is not a standalone condition but rather part of a broader spectrum of post-viral syndromes.

These findings align with previous Australian research published in the American Journal of Medicine in 2023. Adelaide researchers objectively demonstrated that 79% of Long COVID patients met the criteria for postural orthostatic tachycardia syndrome (POTS), an autonomic nervous system disorder. Considering that POTS typically emerges following viral infection, this correlation is not unexpected. However, it’s concerning because POTS significantly impairs quality of life and functional capabilities, particularly affecting women during their childbearing years.

Of further concern is the absence of specialised public autonomic physician training programs in Australia, unlike in the USA. This leaves us ill-equipped to manage the increasing burden of post-COVID chronic autonomic disorders.”

Professor Jeremy Nicholson, a Professor of Medicine and Director of the Australian National Phenome Center at Murdoch University notes that “COVID-19 is a complex respiratory and systemic disease with multi-organ involvement producing a range of severities and secondary complications. A significant number of COVID-19 patients transition to a long-term or persistent form of the disease even after the active virus has departed from the body. This condition has been colloquially termed Long COVID.

As the authors of the new paper state, this is a post-viral syndrome of the sort that has long been recognised for other viral infections including influenza. The question is ‘is long COVID unique, worthy of its own name, or is it just another post viral syndrome’?

The new study reports a year follow-up on 5112 symptomatic adult COVID-19 patients (omicron sub-variant of the SARS CoV-2) and 995 post influenza patients from Queensland Australia. The study indicates that 3-4% of people have significant symptoms a year after either COVID-19 or influenza, hence the authors argue that they are effectively the same.

Unfortunately, this question cannot be simply answered in this work. The study is observational, based on reported symptoms with no physiological or detailed functional follow-up data. Without laboratory pathophysiological assessment of individual patients, it is impossible to say that this is indistinguishable from flu-related or any other post-viral syndrome.

Also, there are many long-term effects of COVID-19 that do not have significant early-stage symptoms e.g. heart disease, atherosclerosis, and diabetes. These conditions do however have associated metabolic signatures which were not measured in the current study.

The absence of evidence is different from evidence of absence- so the authors’ assertion that Long COVID is the same as flu-related post viral syndrome, is not proven, even if Long COVID is indeed a post-viral syndrome (which it is).

What is certainly true is that the pandemic nature of COVID-19 created a huge number (millions of people worldwide) of Long COVID sufferers and that this has drawn attention to the problem and given it a name. But we still do not know whether Long COVID is physiologically or mechanistically different to other post-viral syndromes, we lack the evidence because it has not been studied properly to date. This is important because such pathophysiological mechanistic knowledge is relevant to developing therapies for any post-viral syndrome including Long COVID.

Until this is resolved, we should still use the Long COVID term because it pinpoints exactly the underlying viral cause for a given individual.

Many people with other post-viral conditions do not have an original identifying cause and this has led to the marginalisation of many patients and difficulties in identifying individual treatments; chronic fatigue syndrome being a good example here.

We also know from much larger peer-reviewed epidemiological follow-up studies in the USA and elsewhere, that Long COVID is associated with increases in heart disease and heart disease risk, diabetes, and long-term neurological damage; and these can occur after only a mild primary infection.

COVID-19 was the biggest biological hit taken by humanity in over a hundred years (since the influenza epidemic of 1918) and has caused major long-term impacts on population health profiles and healthcare costs that will also persist for years. We also know that many patients have persistent and profoundly different metabolic biochemistries after acute SARS CoV-2 infections and beyond, which indicates ongoing systemic immuno-metabolic disturbances.

Only by studying these quantifiable perturbations in real populations will we be able to determine if Long COVID is really the same as other post-viral syndromes. Or, if it is immunologically and metabolically different, but still part of an extended spectrum of post-viral syndromes, which will all require their own therapeutic intervention strategies for individual patients. Only further research into the comparative pathophysiology of Long COVID and other post-viral syndromes will answer this question.”