Covid: keeps on getting longer

 A recent Chinese analysis found some significant long-term sequelae from long Covid, 2 years after the initial infection and largely independent of the initial disease severity (see covid long covid 2 years later lancetrespdix2022 in dropbox. or doi.org/10.1016/ S2213-2600(22)00126-6, or https://www.thelancet.com/action/showPdf?pii=S2213-2600%2822%2900126-6). Thanks to Laury Dworet for bringing this to my attention. 

 

Details: 

-- longitudinal cohort study of 2469 individuals who survived hospitalization after Covid infection and were discharged from a hospital in Wuhan, China (Jin Yin-tan Hospital), between January 7 and May 29, 2020 

-- 1192 completed assessments, 94% of whom attended face-to-face interviews 2 years after the infection 

-- median age 57 years, women 46%, current smoker 7%/former smoker 10%/never smoker 82%, hypertension 34%/diabetes 14%/coronary heart disease 9% 

-- ICU admission 4%, with 18-day average length of stay 

-- health outcomes were measured at 6 months, 12 months, and 2 years after symptom onset, including a 6-minute walking distance (6MWD), laboratory tests, and questionnaires on self-reported symptoms/mental health/health-related quality-of-life/return to work/and health care use after discharge 

-- high resolution CT scans were also done on 65 people including at the two-year visit, and 349 had pulmonary function tests (these were done on random sample of those with prior abnormalities)

-- median follow-up time after symptom onset was 185 days for the visit at 6 months, 349 days for the visit at 12 months, and 685 days for the visit at 2 years 

-- patients were stratified by the severity of their initial Covid illness: scale 3 for those not requiring supplemental oxygen, scale 4 for those requiring supplemental oxygen, and scale 5-6 in those requiring high flow mechanical oxygen by nasal cannula, noninvasive mechanical ventilation, or invasive mechanical ventilation

-- primary outcomes: symptoms, modified British Medical Research Council (mMRC) dyspnea scale, 6MWD, health-related quality of life (HRQol, including the EQ-5D-5L and the EuroQol scales), anxiety and depression per the GAD-7, PHQ-9, and the 17-item PCL-C (the civilian version of the PTSD checklist), and percentage returning to work. 

    -- Symptoms, mMRC, dyspnea scale, HRQol were also measured in 3383 age-matched, sex-matched, and comorbidities-matched (cardiovascular disease, chronic respiratory disease, chronic kidney disease, hypertension, and diabetes), community-dwelling participants without Covid, who served as controls 

 

Results: 

-- proportion of Covid survivors with at least one long covid symptom: 

    -- 6-month exam: 777 (68%) 

    -- 12-month exam: 583 (49%) 

    -- 2-year exam: 650 (55%) 

       -- difference over time: statistically significant, p<0.0001 

      -- but, no difference observed across the severity groups of the initial Covid infection

        -- most common symptoms:  

            -- fatigue or muscle weakness: 52% at 6 months, decreasing to 20% at 12 months, and increasing to 30% at 2 years 

            -- sleep difficulties: 27% at 6 months, 17% at 12 months, and increasing to 25% at 2 years 

            -- hair loss: 22% at 6 months, 11% at 12 months, and 12% at 2 years 

            -- smell disorder: 11% at 6 months, 5% at 12 months, 6% at 2 years 

            -- joint pains: 11% at 6 months, 12% at 12 months, and 10% at 2 years 

 

-- mMRC dyspnea scores of at least 1: 26% at 6 months, 30% at 12 months, and 14% at 2 years, p<0.0001 (these percentages were higher as initial covid infection was more severe) 

-- HRQol scores: anxiety and depression decreased from 23% at 6 months to 12% at 2 years, p<0.0001 

-- pain or discomfort scores: 27% at 6 months, 29% at 12 months, and 24% at 2 years 

-- anxiety or depression: 23% at 6 months, 26% at 12 months, and 12% at 2 years 

    -- GAD-7, PHQ-9, and PTSD symptom scores were only measured at 2 years, with prevalences of 8%, 6%, and 2% respectively 

-- mobility problems: 6% at 6 months, 9% at 12 months, and 4% at 2 years

-- 6MWD scores were less than the lower limit of normal in 14%:  

    --overall 495 meters at 6 months, 495m at 12 months, and 512m at 2 years (with no difference based on initial disease severity) 

-- return to work: 89% had returned to their original work at 2 years (those not returning did so for a variety of reasons, including decreased physical function, unwillingness to return to work, and unemployment) 

-- health care utilization: no difference by initial disease severity, outpatient clinic visits in 18%, hospitalization 13%, emergency department visits 1% 

-- survivors with long Covid symptoms at 2 years had lower HRQol, worse exercise capacity, more mental health abnormalities, and increased healthcare use after discharge than survivors without long Covid.  

-- as compared to controls, survivors with long Covid symptoms also had more prevalent symptoms as well as more specific problems in pain or discomfort as well as anxiety and depression, all with p<0.0001. This was also true for problems performing usual activities and EuroQol quality-of-life scores 

-- those with Covid who received higher level respiratory support during hospitalization, versus controls, had more lung diffusion impairment (65% versus 36%, p=0.0009), reduced residual volume (62% versus 20%, p<0.0001) and reduced total lung capacity 39% versus 6% (p<0.0001). Of 57 who had initially abnormal high-resolution chest CT exams at 12 months, 10 achieved complete resolution at 2 years, with the most common remaining imaging abnormalities in those with continued abnormalities being ground glass opacity and irregular lines, largely limited to those with the most severe disease 

 

-- in their detailed table of symptoms (table 2), as mentioned above, there really was not much difference between those who had less severe versus very severe initial covid infection in terms of long Covid symptoms, especially at the two-year mark

 

-- overall results in those with long Covid in multivariate adjustment: 

    -- mobility problems: odds ratio 3.81 (1.62-8.93) 

    -- pain or discomfort: OR 4.42 (3.14-6.21) 

    -- anxiety or depression: OR 7.46 (4.12-13.52)

 

-- in those with long Covid at 2 years, subgroup analysis after multivariate adjustment:

    -- women did worse than men: OR 1.65 (1.41-1.92) for long Covid, OR 1.94 (1.59-2.37) for anxiety or depression, OR 2.86 (1.92-4.26) for lung diffusion impairment  

    -- those with initially more severe disease did have somewhat higher likelihood of the following: long Covid OR 1.40 (1.02-1.91), fatigue or muscle weakness OR 1.45 (1.06-1.98), anxiety or depression 1.54 (1.06-2.22), and lung diffusion abnormality OR 3.14 (1.77-5.59) 

    -- corticosteroid therapy, given to 25% of the patients acutely, was associated with increased long-term risk of fatigue or muscle weakness, OR 1.36 (1.12-1.64) 

 

Commentary: 

-- this study confirmed continued improvement of people over time, up until 2 years after their initial infection, and it extends the results from several one-year studies. This study did involve a large cohort of patients who were the earliest infected with Covid infection, thereby allowing for this assessment of long-term follow-ups. (for the 1-year study from this hospital, see http://gmodestmedblogs.blogspot.com/2021/10/covid-longer-covid-after-1-year.html )

    -- BUT, though decreased overall, there certainly were significant continued symptoms at 2 years in many long Covid patients (about 50% of those with initial symptoms still had symptoms at 2 years). These patients had significantly lower health status, more health care utilization, and decreased quality of life than the general population as well. 

-- The finding of persistent symptoms was also found with the initial SARS outbreak (SARS-CoV-1) 20 years ago, with symptoms persisting for up to four years. It was also notable that the symptoms of post-Covid-19 fatigue did fluctuate over time (eg, several were better at the 12-month assessment, then worse at 2 years).

-- It was perhaps notable that those given corticosteroid therapy in the acute covid infection did seem to have more issues with fatigue or muscle weakness later. A recent article suggested that anti-inflammatory medicines acutely may be associated with more long-term problems (will send out a provocative blog on this soon, a bit of foreshadowing...) 

-- the lack of association between the intensity of the initial infection and long covid symptoms has been noted in several prior studies, including some finding long covid in those with asymptomatic infections. a few prior blogs of note:

    -- http://gmodestmedblogs.blogspot.com/2021/04/covid-long-covid-predictors.html , a study finding that the long covid symptoms may begin weeks after the acute infection resolves

    -- http://gmodestmedblogs.blogspot.com/2021/08/covid-long-covid-update-including-in.html , a study on long covid in kids, including in asymptomatic ones

    -- http://gmodestmedblogs.blogspot.com/2022/01/covid-post-vaccine-infections-long.html, breakthrough infections post-vaccination have a lower rate of long covid

 

Limitations: 

-- only about half of the individuals identified actually completed the 2-year study. there may well have been a large selection bias in those who decided to participate (ie, perhaps participants were more likely to have long Covid than those electing not to participate) 

-- most of the information was self-reported, including comorbidities, the demographics, and many of the clinical outcomes. There may have been inaccuracies in what was reported 

-- the fact that these individuals were hospitalized in China does not necessarily mean that they had severe Covid infection (there was a very low threshold to hospitalize patients early in the pandemic: hence the large numbers of scale 3 patients)

-- there were relatively few patients having the most severe Covid (scale 5-6 category), limiting the statistical significance of some of these findings

-- it is hard to disentangle many of these long-term symptoms as being from the Covid infection itself versus the dramatic changes in people’s lives during the Covid pandemic:

    -- it is likely that those with covid infection experienced even more longer-term dramatic/traumatic effects from the trauma of their prior Covid infection (PTSD-like)

    -- the psychologic effects of Covid (notably anxiety and depression, along with suicidality and substance use) have been much more pronounced during the pandemic, and perhaps more likely in those who had Covid infections, perhaps increasing overall long covid symptoms

    -- all of this was augmented by the pandemic-related social isolation, lockdowns, and financial distress

    -- and the psychological sequelae might even be more pronounced given the attention/perhaps exaggeration paid to covid and long Covid in the public sphere

-- no data on whether patients had had Covid reinfections with other variants during the followup period, though this is less likely in China with its aggressive isolation/mitigation strategies 

    -- Some studies have suggested variability in symptoms by different variants, though I could not find any information about differences in the incidence of long Covid stratified by the different variants (for some of the differences in the specific long covid symptoms by variant type, see https://khn.org/morning-breakout/long-covid-symptoms-might-depend-on-which-variant-you-had-study-finds/ )

-- it is always useful to have a control group of patients living through the pandemic as a comparison, though a more apt comparison might be patients who were hospitalized with respiratory distress from non-Covid reasons 

-- this is also a single center study in China, which might limit generalizability to other areas in China as well as in the rest of the world 

 

So, pretty interesting and scary study. As mentioned, long-SARS-CoV-1 twenty years ago extended up to 4 years after the initial infection (maybe longer for some??). Covid-19 , on the other hand, infected hugely more people, so even if 10% have some long covid symptoms, this translates into huge absolute numbers of people. And long covid-19 is going to last how long???

as found in other studies, long covid does happen about as often in those with mild vs severe infections. which really brings up the issue of younger people feeling that covid is just a bad cold and vaccination is not necessary. we need to figure out how to reach these vaccine-hesitant younger people better.  studies done last year suggested that the issue was largely unfounded fear of adverse effects (eg infertility, computer chips injected into one's body,...), and not rigid political sectarian divisions (more in older folks).  Long covid should be one of the talking points with all unvaccinated, but perhaps especially the poorly vaccinated younger people...

geoff

 

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