An analysis published this week in the British Medical Journal has found that significant flaws in published research on long-Covid meant that its prevalence was overstated, causing “undue concern and anxiety” to the public. Researchers found that the most well designed studies provided reassuring, low estimates of long-lasting Covid symptoms, in contrast to what was reported in the media.
The risk of long Covid was exaggerated because of “overly broad definitions, lack of control groups, inappropriate control groups, and other methodological flaws”, the analysis found.
“This problem is further compounded by inclusion of poorly conducted studies into systematic reviews and meta-analyses that overstate the risk,” researchers concluded. “This is fed to the public by the media and social media, raising undue concern and anxiety.”
The unintended consequences of this may include increased societal anxiety and healthcare spending, a failure to diagnose other treatable conditions misdiagnosed as long COVID, and diversion of funds and attention from those who truly suffer from chronic conditions secondary to COVID-19, the study found.
The peer-reviewed analysis aimed “to discuss these estimation errors and why epidemiologic research on long COVID has been misleading”.
DEFINITIONS
The analysis pointed out that four international health organisations, such as the influential US Centers for Disease Control and Prevention (CDC), and the World Health Organisation, used a definition of long Covid which did not require a causal link with infection with the virus – meaning any new symptoms after confirmed or suspected Covid-19 infection, regardless of their actual cause. could be considered consistent with long COVID.
The researchers said that the CDC’s definition allows any symptom lasting at least 4 weeks after infection with Covid-19 to be included as a long Covid symptom, and sais that this definition was likely to create misclassification bias by making it more likely that a temporally unrelated symptom or condition after Covid-19 infection is “improperly labelled long COVID”.
“In general, in the scientific literature, imprecise definitions have resulted in more than 200 symptoms being associated with the condition termed long COVID,” the analysis found.
“For the purposes of this paper, we define long COVID as a syndrome or individual symptoms which are direct sequelae of the virus, SARS-CoV-2, and last at least 12 weeks,” the researchers said.
They proposed that “future research avoid the umbrella term ‘long COVID’ and instead more narrowly define certain post-COVID syndromes or symptoms (such as anosmia) which may be specific to the SARS-CoV-2 virus.”
CONTROL GROUPS
The analysis was critical of the failure to meet a “most basic obligation” to compare symptoms among Covid-19 cases to a control population – which they said “ideally would be similar to the cases in demographics, underlying health, geography and time.”
“One recent systematic review identified control groups in only 22/194 (11%) of long COVID studies,” they said.
Another systematic review reported a long Covid prevalence of 25% in children but, again, did not consider how prevalent symptoms were in control groups, claimingh that the group itself was diverse, the analysis found.
The same authors also reported a long Covid prevalence of 80% in adults in a 2020 systematic review, the researchers said. “Not only did they not compare cases with controls, but they also included studies with a short median follow-up of only 1 month, studies that did not specify length of follow-up and studies that included abnormal laboratory results as ‘symptoms’. Lack of control groups, convenience sampling and heterogeneity of follow-up time has made drawing conclusions from systematic reviews challenging.”
The pointed out that a Norwegian study of children and young people aged 12–25 used a modified definition for long Covid and found a striking similarity in the prevalence of symptoms in the post-Covid-19 group and the control group.
There were also issues with inappropriately-matched control groups in the studies under review, the researchers said.
“Not only should control groups be included, but they should also be properly matched to cases, ideally by age, sex, geography, socioeconomic status and, if possible, underlying health and health behaviours,” researchers said.
“The CDC, for example, estimated 38% of case-patients experienced an incident condition within a year of COVID-19 diagnosis documented in the electronic health record compared with 16% of controls. However, they failed to acknowledge that those who are diagnosed with COVID-19 in healthcare settings tend to be less healthy at baseline than those who do not seek COVID-19 testing in the healthcare system, which could have biased the estimate by including more severe cases in the post-COVID group and less severe in the controls,” they explained.
“As another example, the US Veterans Affairs (VA) researc has produced misleading results because those who received a diagnosis of COVID-19 through the VA (as opposed to being asymptomatic or mildly asymptomatic and testing at home or not testing at all) have fundamentally different health status than controls. The authors themselves described the cases as being predominantly white, male, older, more obese, on multiple regular medications and having poorer underlying health than the general population; thus, it was expected they would also have very high rates of multiple symptoms and outpatient encounters post-COVID-19.”
WELL-DESIGNED STUDIES REASSURING
The analysis found that in the UK, national surveys conducted by the Office for National Statistics (ONS) continue to report a 2.9% prevalence of self-reported long COVID in adults and children.
They noted that, even with that low prevalence, when a control group was included with age, sex, health and socio-demographically matched controls, the prevalence of any of 12 common symptoms was 5.0% at 12–16 weeks after infection compared with 3.4% in a control group with people who had not been diagnosed with Covid-19 , demonstrating the relative commonness of these symptoms in the population at any given time.
“Notably, too, this national study was performed prior to the omicron variant, which has been associated with significantly lower prevalence of persistent symptoms compared with previous variants, with one UK study estimating 0·24–0·50 odds of long COVID with the omicron versus the delta variant,” they said.
“Supporting these findings, a well designed Swiss study used antibody seroconversion during the study period to confirm SARS-CoV-2 infection in children. In randomly assigned school classes at the end of 2020, they found essentially the same prevalence of lasting symptoms among 12-16 year olds who had been infected compared with those who had not been,” they added.
“It is noteworthy that the findings of the highest-quality research stand in contrast to much of what is reported in the media.” Such high-quality studies can and should be used to reassure the public about the risks of long Covid, the analysis found.
RECOMMENDATIONS
The paper recommended, in addition to including appropriately-matched controls, better case definitions and more stringent long Covid criteria, “which should include continuous symptoms after confirmed SARS-CoV-2 infection and take into consideration baseline characteristics, including physical and mental health, which may contribute to an individual’s post-COVID experience”.
It was noted that: “When limiting studies to those with acceptable PASC definitions and appropriate controls, we find little to no difference in the prevalence of reported persistent symptoms in children by 4 weeks or in adults younger than 50 years by 12 weeks post-infection compared with controls.”
“It is noteworthy that the findings of the highest-quality research stand in contrast to much of what is reported in the media. Such high-quality studies can and should be used to reassure the public”, the researchers said. .
“In summary, the results of well designed population-based studies of long COVID in adults and children have been reassuring. However, taken together, the existing literature is replete with studies with critical biases that clinicians and researchers alike should be aware of,” they concluded.