A study published in JAMA Internal Medicine looks at the association of self-reported COVID-19 infection and antibody test results with persistent physical symptoms among French adults during the COVID-19 pandemic.
Dr David Strain, Senior Clinical Lecturer, University of Exeter, said:
“This manuscript uses a large French database to explore the occurrence of “long COVID” symptoms in a population who had experienced symptoms compatible with COVID, and those who had confirmed COVID and those who only discovered they had been exposed to COVID by serology (blood testing) during this screening program. It demonstrates that the belief of an infection with COVID was the most important predictor of ongoing symptoms, more so even than having had a serological confirmation of the infection. The only exception to this is the continuation of anosmia (lack of sense of smell), which does appear to be a COVID/Long-COVID specific symptom. The authors conclude that there may be other mechanisms at play regarding the causes of long COVID.
“It misses a very simple explanation. Whether the participants had COVID or not, there is no doubt that they were experiencing some illness that they attributed to COVID. There are multiple viral illness other than COVID that cause “long symptoms”. Historically these symptoms may have been labelled a post viral fatigue, or in more extreme cases Myalgic Encephamlomyelitis (ME). These diagnoses have been surrounded in stigma and therefore people may do not come forward with their symptoms or have them recognised.
“Alternatively, the preconception by many, that COVID is the only viral illness that causes these ongoing problems, may have led many to assume their initial illness was COVID based on the presence of their long symptoms. The acceptance of long-COVID as a post viral syndrome has allowed many people to have their conditions recognised, and hopefully will lead to wider research opportunities in related conditions such as ME.”
Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:
“This looks as if it’s an interesting study – and indeed it is interesting, but it’s potentially very misleading to take its results at face value. On the face of it, the conclusions look as if they are saying that persistent physical symptoms, of the sort often associated with ‘long Covid’, are more strongly associated with believing that one had Covid previously, that they are with having had a particular kind of positive test for antibodies from an infection with the SARS-CoV-2 virus. This could be taken to mean that the presence of these symptoms could be more affected by what people believe happened to them than by what previously happened to them as recorded by a test. That does remain a possibility in the light of these results, but it’s very far from being the only possibility.
“One basic issue is that this is an observational study, and it’s never possible to be certain about what causes what in observational studies. While that’s always true in any observational study, there are some characteristics of this one that make it a particularly important issue here. There’s no direct way to tell whether the people in the study, who believe they have previously had Covid, believe that because they have long-lasting symptoms – that is, the symptoms caused the belief – or whether it’s the other way round, and having people who started off believing that they had previously had Covid, then are more likely to report long-lasting symptoms – that is, the belief caused the symptoms. Or, probably more likely that both of those possibilities, it could be a mixture of the two. What’s more, in this study, the participants already knew the result of their serology (antibody) test when they were asked the questions about whether they thought they had had Covid previously and about their symptoms. So they are unlikely to be typical of people in the general French population who would, mostly, not have had an antibody test at all. This study therefore makes it difficult to draw general conclusions about how these things might work in the French population generally (let alone any other population), or to draw any clear conclusions about cause and effect.
“Another issue about the general applicability of the findings is that these results are based on findings from a subset of a large population cohort study, that looks at volunteers aged 18-69 from the French population. I do not know all the details of this cohort study, the CONSTANCES study, but in general people who volunteer for a study like this, which is explicitly about health, is that they tend to be more interested in matters of health than is the population generally. That’s inevitable – but it could be a particular issue when, as here, one is studying something that could possibly depend on people’s attitudes about their own health. Further, the participants in this new piece of research seem not to be particularly typical of the whole CONSTANCES cohort in some ways.
“There are also issues about the serology test that was used. Generally the report is written with a mostly implicit assumption that the people who tested positive for antibodies on the serology test definitely had been previously infected, while those who tested negative had not been infected. The researcher do acknowledge that that isn’t the case – in the part of the Discussion section of their report about Strengths and Limitations, they rightly acknowledge that the antibody test might, in some cases, not actually correspond to whether people had really been infected. That’s always the case for any diagnostic test of this sort, because no such test is perfect. The researchers provide arguments to support their belief that this is not in fact a big problem in this study – but errors in diagnostic test results are often counter-intuitive, and I don’t entirely agree with the researchers’ conclusion. They do correctly point out that, with an assumed prevalence of previous infection of 4%, and the performance rates for the test that they quoted earlier in their report, they would expect 139 participants to be false negatives (that is, they had a negative antibody test results but did actually have a previous infection), and they rightly point out that this is less than 1% of those who tested negative. What they don’t do is look at false positives – with the assumptions they make, there would be rather a lot of false positives, in fact about 644 of them, which would be about four in every ten people who test positive for antibodies. That is, quite a big proportion of those who had a positive serology result would not in fact have been infected – and in a study that is comparing how closely test results align to symptoms, false positives can matter too.
“On a related point, I think there could be some issues with the assumptions behind these calculations anyway. First, the figures for the performance rates (sensitivity and specificity) of the antibody test come from a study which did report on the same laboratory assay as in this new research, but the samples that were used in that study came from stored blood plasma and not, as here, dried blood spots. I’m not enough of an expert on these tests to be able to say whether than would make an important difference, but perhaps it would. Then, the researchers do not say where their figure of 4% prevalence of previous infection comes from. In the people actually included in their statistical analysis, a little under 2% had a positive antibody test result. That’s a much lower figure than you would get with 4% prevalence and the stated performance rates. Indeed, the researchers are assuming a specificity of 97.5%, which means that, of all the people who really never had Covid, 2.5% would produce a positive test result anyway (and so be false positives). So the data that they report are actually consistent with all the people who tested positive being false positives. I don’t believe for a minute that they are in fact all false positives – but this does indicate that the assumptions behind the performance of the test and about possible misclassification of who was previously infected are unlikely to be correct, and that can feed through into the interpretation of the results.
“I’m not trying to trash this research. These things are difficult to study and this new study does provide potentially useful information. The results are compatible with the possibility that some people, who have long-lasting symptoms of the sort attributed to long Covid, perhaps never had Covid, so that their symptoms arise through some other mechanism. But I don’t feel that this research can give a clear enough indication of how likely this is. The conclusions to the research do suggest that the diagnosis and treatment of people who have this kind of symptom should at least consider other possibilities rather than always assuming everything was directly caused by the virus. That sounds reasonable – it’s never good for clinicians to rule out alternative explanations too quickly, I’d say. But, even if someone does have distressing symptoms, after they believe they had Covid, and in fact it turns out that symptoms have some other cause than the virus, that doesn’t mean that the symptoms don’t require treatment. The relatively high prevalence of this kind of symptom would be important in planning and resourcing health services anyway.”
Dr Jeremy Rossman, Honorary Senior Lecturer in Virology, University of Kent, said:
“The study by Matta et al. looks at the correlation between self-reported COVID-19 infection, antibodies to SARS-CoV-2 and Long COVID symptoms. The authors conclude that the belief in COVID-19 infection is associated with persistent symptoms, but not the presence of antibodies to the virus or having a positive diagnostic test. However, there are several concerns with this analysis.
“First, a serological test for the presence of COVID-19 antibodies is an unreliable marker for previous infection, and some research in hospitalised patients suggests Long COVID patients can tend to have weaker antibody responses (García-Abellá, J Clin Immunol 2021; https://link.springer.com/article/10.1007/s10875-021-01083-7). In addition, antibody levels diminish over time and the study did not report on the duration between reported infection and the serological test. Furthermore, the authors report that only anosmia (or loss of smell) was associated with a positive serological test, but anosmia tends to be one of the shorter duration symptoms of Long COVID and thus, patients still experiencing anosmia may have been more recently infected and thus more likely to have detectable antibody levels.
“Second, the authors state that having a confirmatory diagnostic test or diagnosis of COVID was only associated with anosmia and not any other Long COVID symptoms. However, in their analysis, the authors compare the likelihood of different Long COVID symptoms in people that believe they had been infected but have not had a diagnostic test with those that believe they were infected and had diagnostic confirmation. Thus, the 15 symptom categories the authors found to be associated with belief in having previously been infected are present in both patients with a positive diagnostic test and those without. If belief, specifically, was driving Long COVID symptoms, then having that belief confirmed would likely increase the odds of having those persistent symptoms. In this study, a confirmatory diagnostic test had no impact on the likelihood of having most Long COVID symptoms, suggesting that belief in having been infected is as accurate as having had a diagnostic test, a result that has been seen in other Long COVID studies.
“The authors conclude that “the belief in having had COVID-19 infection may have increased the likelihood of symptoms, either directly by affecting perception or indirectly by prompting maladaptive health behaviors, such as physical activity reduction or dietary exclusion”. This conclusion reiterates a damaging narrative, implying that Long COVID is a psychological disease and that by taking steps to avoid symptom exacerbation patients are effectively making themselves sick. This is a narrative that Long COVID patients, advocates, physicians and scientist have been struggling to address in many countries around the world. There are multiple studies that demonstrate the presence of persistent physiological symptoms following SARS-CoV-2 infection that are not present in uninfected controls.”
‘Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic’ by Joane Matta et al. was published in JAMA Internal Medicine at 16:00 UK time on Monday 8 November 2021.
All our previous output on this subject can be seen at this weblink:
Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee. I am also a member of the Public Data Advisory Group, which provides expert advice to the Cabinet Office on aspects of public understanding of data during the pandemic. My quote above is in my capacity as an independent professional statistician.”
Dr Jeremy Rossman: “I am an honorary Senior Lecturer in Virology and the President of Research-Aid Networks, a non-profit organisation that works with Long COVID patient associations on research and scientific communication.”
None others received.