Long COVID patients continue to experience significant symptoms at 12 months and factors associated with improvement: France PERSICOR, 2023, Salmon et

[SNT Gatchaman]

Long COVID patients continue to experience significant symptoms at 12 months and factors associated with improvement: a prospective cohort study in France PERSICOR
Salmon; Slama; Linard; Dumesges; Lebaut; Hakim; Oustric; Seyrat; Thoreux; Marshall

Objectives
This study examines long COVID symptoms course over 12-months, their impact on daily life, and associated factors for symptom relief.

Methods
A prospective cohort study included 231 participants with long COVID at 12-months follow-up. Data on characteristics, symptom course and remission were collected using questionnaire and a remission scale. Poisson regression models were used to estimate the prevalence rate ratio (PRR) and 95% confidence intervals (CIs) for factors associated with symptom improvement.

Results
Of the 231 participants, 63.2% developed SARS-CoV-2 antibodies before COVID-19 vaccination. At 12-months, only 8.7% (95% CI: 5.4%-13.1%). reported complete remission, while 28.6% noted significant improvement. Most symptoms remained prevalent: asthenia (83.1%), neurocognitive/neurological (93.9%), cardiothoracic (77.9%), Musculoskeletal (78.8%). During long COVID, 62.2% stopped working, and only 32.5% resumed full-time professional activities. Presence of SARSCoV-2 antibodies before vaccination increased the probability of improvement (aPRR: 1.60, p=0.028), while ageusia at initial long COVID phase decreased the probability (aPRR: 0.38, p=0.007).

Conclusions
Long-COVID symptoms persisted in the majority of participants after 12-months, with significant impacts on daily life and work. SARS-CoV-2 antibodies were associated with better prognosis, while persistent ageusia indicated a lower probability of improvement. These findings highlight the need for ongoing support and care for individuals with long-COVID.

Highlights

• Long COVID patients tend to have persistent symptoms at 12-month

• At 12-month only 8.7% of Long COVID patients are in complete remission

• There is profound impact on daily life, work and daily activities

• SARS-CoV-2 antibodies prior to vaccination appears to be linked with better recovery

• Ageusia is associated with reduced chances of improvement at 12 months

Link | PDF (International Journal of Infectious Diseases)

 

[NelliePledge]

Ageusia is loss of taste for those like me who hadn’t heard of it before.

 

[Hutan]

A dedicated Long COVID clinic has been operational since May 2020 at Hotel Dieu in Paris, affiliated with the Greater Paris Public Hospital.

Patients received a comprehensive medical evaluation, including physical and biological examinations. A standardized questionnaire gathered baseline data

Patients attending this consultation were invited to participate in an observational study called PERSICOR previously described [5] if they had the following inclusion criteria: age> 18, documented or probable acute infection as defined by WHO COVID-19 Case definition[22]; at least two persistent or recurrent symptoms lasting for more than 2 months and occurring in the 3 months following initial COVID infection and absence of another obvious cause of symptoms, a definition corresponding to the WHO post COVID-19 condition definition

To be included in this sub-analysis, participants were selected from the PERSICOR as ambulatory long COVID-19 patients, having their first COVID-19 episode between January15, 2020 and October 18, 2021.

This sub-study was organized with two visits and at each visit, a specific standardized questionnaires was completed. The 1st visit was a presential visit (1st consultation) and at this visit, data on acute infection and onset of long COVID period were collected. The 2nd visit was done at 12 months +/- 1 month after the first consultation via a presential or via an online questionnaire for those who would not come to the consultation.

 

[Hutan]

Of 307 Long COVID patients included and who reached the one-year follow-up point, 296 were successfully recontacted. Of those contacted, 65 did not participated to the survey and 231(78%) completing a 12-month follow-up questionnaire.

So, a significant loss to followup.

Median age was 45 years (IQR:38-53), 77.5% were female, 57.6% had a history of atopy, allergy, or asthma, and 24.7% an history of depression or anxiety prior to the pandemic. Additionally, 23.8% of participants reported an autoimmune disease (personal 17.3% and/or familial 13.8%). Only 53 participants (22.9%) had been hospitalized during their acute infection, and 8(3.5%) experienced reinfections following their initial COVID-19 episode.

Mostly female.

A free interval between acute infection and onset of long COVID was reported for 46% and the median delay of this free interval was 1.0 months (IQR:0-2.0).

I'm not sure how to explain the 1 month delay in Long Covid onset in nearly half of the participants. Does an immunological pathology take time to set in for these people? Or is it just that the person has rested during the acute phase, and taken some time to get back into their usual activities And it's only then, when they try working again, when it is clear that they aren't functioning as they did?

The median delay from acute infection to first consultation in long COVID clinic was 4.6 months (IQR:2.2-8.7), and the median delay between the first consultation in long COVID clinic and the 12-month questionnaire was 12.6 months (IQR:11-13).

So, roughly, this followup assessment is at 1.5 years.

 

[Hutan]

Overall, 146(63.2%) tested positive for SARS-CoV-2 antibodies, 83(35.9%) tested negative, 2(0.9%) had not taken a test. The median time between acute infection and the serological test was 2.5 months (IQR:1.9-3.3).

Most of these people without antibodies had compelling evidence to suggest that they had indeed had the infection.

At the 12-month follow-up, the median of post-COVID-19 condition self-assessment score was 7(IQR:6-8). Supplementary materials F provides cumulative percentages of participants reporting complete symptom remission (score at 10). The cumulative percentages of complete remission at 12 months were 8.7%(95%CI:5.4%-13.1%). A significant improvement (score at 8-9) was reported by 28.6% while 62.7% reported minor or no significant improvement in symptoms (score < 8).

Regarding the impact on daily life (Table 3), 62.2% of participants (120/193) who had been employed before their acute infection had to discontinue their work during long COVID phase. Among those who stopped working, only 66.7%(80/120) resumed their professional activities. Only 58%(47/80) of those who had ceased working were back to full-time employment at one year.

There's a bit of an issue with that last sentence, as not all of the people who had ceased working were working full-time before becoming ill. So, we wouldn't expect them to necessarily take up full-time paid employment upon return to full health. The data reported don't tell us what decrease in paid employment hours have been experienced across the cohort.

Regarding routine domestic activities, 24.7% of participants were able to resume them after 12 months. For sports activities, 29% could engage them without any difficulty. A worrying picture also emerged regarding driving without difficulties (64.5%), reading without difficulties (59.7%).

That 24.7% of participants being able to resume routine domestic activities is very concerning at first look. However, it is a very unclear statistic.

Resumption of domestic activities at one year (n=231)
No 25.1%
Part-time 50.2%
Full-time 24.7%

It looks as though the 24.7% is people who have returned to full-time routine domestic activities. So, people who are working in paid employment wouldn't be in that category. I think it would be more accurate to say that 75% of the participants in the followup had resumed domestic activities 1.5 years after onset. But, even that doesn't tell us much - have they resumed all of their domestic activities? Or are they just wiping the kitchen bench every now and then?


For the 'ability to drive' question, the denominator is the full 231 participants of the study. So, it isn't clear if some people unable to drive after Long covid were also unable to drive before the study. Nevertheless, there's still a really large percentage of participants who reported that driving was difficult (42.4%).

 

[SNT Gatchaman]

I'm not sure how to explain the 1 month delay in Long Covid onset in nearly half of the participants. Does an immunological pathology take time to set information these people? Or is it just that the person has rested during the acute phase, and taken some time to get back into their usual activities And it's only then, when they try working again, when it is clear that they aren't functioning as they did?

This is relatively commonly described in our local FB support group, where people had recovered completely from a mild infection and a few weeks later started developing symptoms of fatigue, exertion and orthostatic intolerance etc.

This matches my own experience. I first noticed cardiorespiratory abnormalities in mid Jan 2021, but in retrospect was showing evidence of exertion intolerance from early Nov/Dec 2020 (which I didn't recognise at the time). There was zero community transmission of Covid in NZ over those months, so the latest I could have sustained an asymptomatic infection was the tail end of a (modest) wave in Aug/Sep 2020.

---
Speculatively and purely looking at the muscle fibre and capillary findings being reported in LC, perhaps the sequence is as follows. Some form of immunometabolic dysfunction is set up (TBA). Capillary flow is impaired, in association with abnormal macrophage infiltration, with damaged and regenerating capillaries that lead to increased basement membrane thickness as a feature. Oxygen diffusion to muscle mitochondria is impaired. Initially metabolically compensated, this leads to increased mitochondrial defects over time that are then symptomatic.

(Perhaps HIF-1⍺ inducing WASF3 could be part of this mechanistic progression. HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions (2012, International Journal of Cancer))

 

[EndME]

I'm not sure how to explain the 1 month delay in Long Covid onset in nearly half of the participants. Does an immunological pathology take time to set in for these people? Or is it just that the person has rested during the acute phase, and taken some time to get back into their usual activities And it's only then, when they try working again, when it is clear that they aren't functioning as they did?

This is relatively commonly described in our local FB support group, where people had recovered completely from a mild infection and a few weeks later started developing symptoms of fatigue, exertion and orthostatic intolerance etc.

This matches my own experience.

It also matches what I've heard amongst patients in the ME/CFS and neurocognitive subset of LC patients and it is the exact same thing that happened to me. I also always fully recovered from the acute Covid phase and only later developed symptoms of LC/ME/CFS. Retrospectively one might say that there were some mild lingering symptoms, but IMO that is incorrect since it suffers from a lot of bias confirmation if one later develops an illness and in the time between acute Covid and onset of LC/ME/CFS I would have always considered myself fully recovered and also was so based on all available data (working full time, doing sports daily etc). At least for me and those that I've talked to, this had nothing to with taking some time off or something similar.

Nath also discussed these 2 distinct patterns in the recent Advancing ME/CFS Research: Identifying Targets for Intervention and Learning from Long COVID conference (https://videocast.nih.gov/watch=52631). This picture summarises the situation well.



Belonging to the second pattern I'm naturally somewhat biased, but I think research has far to heavily focused on the first pattern and should have explored the second pattern much more. The second pattern automatically excludes the whole PICS, organ damage, pre-existing health anxiety, a continuing cough, anosmia, self-resolving fatigue or similar symptomology that isn't related to what one actually wants to study when studying LC or long-term health outcomes. Compared to the first pattern, there might be a somewhat bigger risk that studying the second pattern also includes some people who have developed problems that could have developed independently of Covid, however choosing previously very healthy people would reduce this risk substantially and the noise reduction of this cohort is well worth it receiving far more attention.

It is quite interesting that people have "brain fog" during acute Covid, then have no problems whatsoever for a number of weeks, and then practically develop "brain fog" overnight a few weeks later. The neurological symptoms of Long-Covid, as well as other symptoms which are considered to be long-lasting on average also begin weeks after the acute phase (there's a couple of studies that explored this for instance https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/fulltext# and https://www.bmj.com/content/380/bmj-2022-072529).

One beautiful aspect of the second pattern is that it completely falsifies the BPS narrative of "these people have illness beliefs caused by an acute infection and then perpetuated by some mind-body connection", because in fact the acute infection was never a problem, there was no anxiety about the acute infection or mind-body manifestation of it and they fully recovered from it.

If not more focus is placed on this second pattern in the future, then I at least hope that future studies would account for these patterns as part of their data when they recruit their patients.

I don't have much knowledge on something like autoimmunity or different immunological processes, but from what I've understood it is almost impossible that these develops within a day or 2 (which some people in the first pattern or those with post-vacc describe) and certainly seems to be far better matched in the second pattern which Nath describes.