September 7, 2022

expert reaction to study looking at depression, anxiety, worry, perceived stress, and loneliness prior to infection with risk of post–COVID-19 conditions

A study published in JAMA Psychiatry, looked at depression, anxiety, worry, perceived stress, and loneliness prior to infection with risk of post–COVID-19 conditions.

Prof Claire Steves, Professor of Ageing and Health, King’s College London, said:

“It’s a very similar design and findings to our paper from the National Core Studies for health and wellbeing here in the UK, which looked at multiple longitudinal population studies with data on prior conditions and looked at risk of long Covid.  In this study too we found a similar increase in odds of developing the condition if individuals had prior anxiety and depression symptoms, or, in electronic health records, diagnoses.  We also showed a range of other independent risk factors.

“So this study replicates previous findings.  Together this shows that we need to pay particular attention to looking after this group as they are more vulnerable.”

Prof Michael Sharpe, Professor of Psychological Medicine, University of Oxford, said:

“This large prospective study of more than 50,000 predominantly female adults from the USA found that those with symptoms of depression, anxiety, worry about covid, loneliness and feeling of being stressed before they were became ill with covid, were more likely to develop prolonged symptoms after covid, a condition sometimes called ‘long covid’.  Whilst the findings do not tell us why these psychological factors predict the development of prolonged symptoms, they do remind us of the medical principle of considering both ‘seed and soil’ .  That is whilst persisting symptoms tend to be attributed to the ‘seed’ of an acute event such as an infection or injury, the ‘soil’ of the individuals vulnerability to developing persistent illness is also important.  These findings also suggest a role of psychological interventions in the prevention and possibly treatment of prolonged symptoms after acute infections such as covid.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This study uses a fairly large number of participants (over 3,000) who reported a positive Covid test and hence might possibly have had ‘long Covid’ by the definition used here, and it used appropriate statistical methods.  Those participants were drawn from a much larger pool of almost 55,000 people, but it’s only the 3,000 who contributed to the results so that’s the number that matters.  But anyway it’s really important not to over-interpret the results.

“The study did demonstrate that there’s a statistical association between reporting various signs of psychological distress before having Covid, and reporting Covid-like symptoms that went on for at least four weeks after an initial Covid infection.  But an association, a correlation, doesn’t establish cause and effect.  It remains possible that having psychological distress before Covid does cause the risk of long Covid to increase, but that’s only a possibility and there are other potential explanations.  The researchers, rightly, do not go further than saying that preinfection psychological distress may be a risk factor for long Covid, not that it is a risk factor.  They finish by concluding that “Future work should examine the biobehavioral mechanism linking psychological distress with persistent postinfection problems.”  This may be going a little too far, in my opinion, because it implies that there is such a mechanism, and that it involves behavioural as well as biological aspects – I don’t think the study establishes that for certain, though it certainly remains a possibility.

“The study is observational, and almost every observational study has problems in establishing cause and effect.  The problem is that the people who reported signs of psychological distress before their infection were, inevitably, different in several ways from the people who didn’t report such signs.  (The types of psychological distress that were investigated were depression, anxiety, worry about Covid, perceived stress and loneliness, though these were determined from the answers to a questionnaire, not from clinical diagnoses of the conditions.)  Any of these other differences might have been the cause of the increased risk of continuing Covid symptoms, and it remains possible that the psychological distress itself played little or no role in increasing the risk.  Of course, the researchers were aware of this issue.  It’s possible to make statistical adjustments to allow for some of these other differences between the people who reported signs of distress and those who didn’t, and the researchers did just that for a substantial set of relevant factors (age, sex, ethnicity, their partner’s level of education, whether they were a health care worker at the start of this new study, whether they smoked, their BMI, and whether they had various pre-existing health conditions).  But one can never be certain that everything relevant has been taken into account, and in any case adjustments can’t be made for factors on which the researchers have no data.

“One possibility that occurred to me is that, though the great majority of participants became eligible for this study because they originally worked in health care, generally as nurses, there was no adjustment for the area of health care or of other work in which they were working during this study.  (There was an adjustment for whether or not they were still in health care at all.)  I don’t think it is out of the question that people working in some areas of health care might be more susceptible to psychological distress than people working in other areas, and that something about the area of work might also, independently, affect who suffers from long Covid.  For instance, those still working in certain areas of health case may have had greater cause to worry about Covid than those still working in some other areas of health, and maybe the area of work somehow affects the chance of continuing symptoms.  In that case this aspect of work might be the real cause of the observed association, rather than the psychological distress itself.  I’m certainly not claiming that this must have happened, but if it’s a possibility, or if there are other similar possibilities, that gets in the way of understanding whether the pre-infection distress is actually causing the increased risk of long Covid.  We just can’t tell, so that the pattern of cause and effect is inevitably uncertain.

“The pattern of association is certainly interesting, though, and perhaps it’s particularly important that the new research observed a stronger association between pre-infection psychological distress and some risk factors for long Covid that have appeared in previous research, such as smoking, pre-existing diabetes, high blood pressure and asthma.  And the researchers do describe a mechanism by which pre-infection distress could be biologically linked to continuing Covid symptoms, via inflammation, though this study can’t possibly provide any direct evidence that that is actually what is going on.

“It’s also very important to point out that the existence in this study of an association between pre-infection psychological distress and post-Covid symptoms does not mean that the study should be interpreted as providing evidence that those long Covid symptoms are somehow all in the mind.  The researchers give several reasons why this is not true – for example, among the participants in this study who did show longer-term post-Covid symptoms, over four in every ten reported no psychological distress before their infection, and the authors point out that the symptoms of long Covid differ considerably from the symptoms of mental illness.

“As well as the overall issue that this is an observational study and such studies make it very difficult to establish cause and effect, the researchers point out some other limitations.  For example, because the participants were drawn from pre-existing studies that mostly targeted people who were nurses when they were recruited, the demographics of the participants were not at all typical of the wider US population, and things may look a lot different in other parts of the population (or indeed in other populations).  For instance, 96% of the group from which the participants were drawn was of White ethnicity, 97% were female, and 38% were currently working in health care.  And all the classifications of people as having psychological distress, as having had a positive Covid test result, and as having continuing symptoms after infection, were based on self-report via questionnaires.  It might well be unlikely that these findings are affected much by misreporting by the participants, and anyway it’s difficult to see what other way of measuring the signs and symptoms could have practically been used, but we can’t be sure whether misreporting played a role.”

Comment gathered by our friends at the Spanish SMC:

Prof Eduard Vieta, Scientific Director of CIBERSAM, Head of the Psychiatry and Psychology Department at the Hospital Clínic de Barcelona and lecturer at the University of Barcelona, said:

“The article is based on an interesting study, which supports the well-known idea that infectious pathologies and their sequelae are influenced by the previous state of the subjects.  In this sense, psychological stress, manifested mainly in the form of anxiety or depressive symptoms, is a risk factor for multiple medical conditions and persistent covid is no exception.  However, the very definition of persistent covid is controversial – it is currently being worked on at the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) in a collaborative effort of elite researchers from various fields, including mental health.

“Thus, a certain tautology/obviousness cannot be ruled out in that the presence of depressive symptoms prior to covid are predictors of very similar and persistent symptoms after infection.  Although the authors attempt to control for this effect, the presence of fatigue and concentration difficulties, cardinal symptoms of persistent covid, are also very common in depression.  In summary, the work is interesting but has limitations and despite these it seems logical to think that previous psychological stress is associated with an increased risk of symptoms, especially neuropsychiatric symptoms, persisting after infection”

‘Associations of Depression, Anxiety,Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post–COVID-19 Conditions’ by Siwen Wang et al. was published in JAMA Psychiatry at 16:00 UK time on Wednesday 7 September 2022.

DOI: 10.1001/jamapsychiatry.2022.2640

Declared interests

Prof Michael Sharpe: “No conflicts.”

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  My quote above is in my capacity as an independent professional statistician.”

For all other experts, no reply to our request for DOIs was received.