Today in Nature Communications, Canadian researchers highlight diagnostic challenges with the World Health Organization's clinical definition of long COVID, with a study showing that over a third of previously infected emergency department (ED) patients met the criteria—as did a fifth of those who reported no history of infection.
And a related systematic review and meta-analysis by Australian researchers finds that 51% of long-COVID patients also met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The research was published yesterday in the Journal of Infection. ME/CFS is a complex, long-term illness characterized by extreme fatigue aggravated by physical or mental activity.
Current definition may lead to overdiagnosis
For the first study, a team led by Universite Laval researchers in Quebec compared the percentage of ED patients with confirmed COVID-19 infection who satisfied long-COVID requirements 3, 6, and 12 months later with those without confirmed infection during the same period.
"In 2024, fewer people are seeking or being offered diagnostic testing for SARS-CoV-2 now that the virus is less virulent and endemic," the study authors wrote. "As a result, people who were never tested for SARS-CoV-2 infection may develop WHO PCC [post-COVID-19 condition] criteria without ever being diagnosed with SARS-CoV-2."
A total of 58.5% of 6,723 eligible ED patients had tested positive for COVID-19 at least 3 months before, 50.6% were women, and the average age was 54.4 years.
Of COVID-19 survivors, 38.9% reported at least one long-COVID symptom at 3 months, compared with 20.7% of those who tested negative. Infected women reported long-COVID symptoms more often than men (45.5% vs 32.8%). By 6 months, 38.2% of infected patients reported one or more symptoms, relative to 19.5% of uninfected participants.
Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition [PCC] become available for diagnosis and treatment.
By 12 months, 33.1% of COVID-19 patients had at least one long-COVID symptom, compared with 17.3% of their uninfected peers. At that time point, relative to the percentage of symptomatic participants at 3 months, those with at least one persistent symptom had decreased 5.8% and 3.4%, respectively.
The number of COVID-19 vaccine doses and types and time since last dose didn't differ among COVID-positive patients with or without long COVID. Similarly, among COVID-negative participants, there were no differences in types of vaccines received before the ED visit or number of days since the last dose.
Infected participants reported each long-COVID symptom at least twice as often as uninfected patients. Few COVID-negative patients reported loss of smell or taste or new chronic cough. A total of 21.4% of COVID-19 patients reported at least three long-COVID symptoms, compared with 6.1% of the uninfected.
Participants infected during SARS-CoV-2 Omicron variant predominance reported more memory impairment, difficulty concentrating, and dizziness than those infected pre-Omicron.
Risk factors for long COVID were a positive COVID-19 test at the initial ED visit, (adjusted odds ratio [aOR], 4.42), admission to an intensive care unit (aOR, 1.84), female sex (aOR, 1.51), loss of smell or taste at the index ED visit (aOR, 1.38), treatment with the anti-inflammatory drug dexamethasone (aOR, 1.27), fatigue at the ED visit (aOR, 1.17), and arrival by ambulance (aOR, 1.16). Vaccination appeared to have no effect on long-COVID risk (aOR, 1.00).
Serologic testing or use of a biomarker for an underlying process related to long COVID, along with a more specific WHO definition, may be needed, the authors said. Abnormal taste or smell, in addition to new persistent cough, and shortness of breath, may also help distinguish long COVID from other illnesses.
"Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition [PCC] become available for diagnosis and treatment," they wrote. "The current WHO definition for suspected SARS-CoV-2 infections will lead to overdiagnosis of PCC among patients with suspected infections who are currently not being tested."
Biomarkers, refined definition may aid diagnosis
The meta-analysis, conducted by Deakin University researchers in Victoria, Australia, estimated rates of ME/CFS among 1,973 long-COVID patients included in 13 clinical studies published from January 2020 to May 2023. The average proportion of women was 78.2%, and the median follow-up period was 7 months.
"Prior to LC [long COVID], long-term debilitating post-viral syndromes have been widely described," the researchers wrote. "For example, viral infections have been associated with approximately 60-70% of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) cases." Associated pathogens include Epstein-Barr, Ross River, human herpesvirus, mycoplasma, influenza A, coronavirus, West Nile, and dengue.
As LC research gains momentum, there will be significant advantages to be leveraged by drawing on over 4 decades of ME/CFS research.
An estimated 51% of long-COVID patients satisfied ME/CFS diagnostic criteria. The most common symptoms were fatigue, sleep disruptions, and muscle or joint pain, and long-COVID patients also had the characteristic ME/CFS symptom of post-exertional malaise.
"Our study not only demonstrates that LC patients exhibit similar symptom clusters to ME/CFS, but that approximately half of LC patients satisfy a diagnosis of ME/CFS," the researchers wrote. "Our findings suggest that current ME/CFS criteria could be adapted to the identification of a subset of LC patients that may facilitate the standardized diagnosis, management and the recruitment for clinical studies in the future."
The authors, however, also noted that a wide range of long-COVID diagnostic and evaluation tools used in the studies may have led to clinical variability and high overall heterogeneity. A number of blood biomarkers seen in some studies may correlate with ME/CFS and long COVID, but larger studies are needed to determine their diagnostic or prognostic value, they said.
"As LC research gains momentum, there will be significant advantages to be leveraged by drawing on over 4 decades of ME/CFS research," they wrote. "While some investigators are initiating LC trials that build on previous ME/CFS findings, LC research has, so far, largely overlooked the ME/CFS field."
