Covid: longer covid, after 1 year

 

A new study assessed the one-year outcome of hospital survivors in China who had had Covid-19 (see covid 1 yr outcome after hosp lancet2021 in dropbox, or doi.org/10.1016/S0140-6736(21)01755-4) 

 

Details: 

-- 1276 Covid-19 survivors who were in the Jin-Yin-Tan hospital between January 7 and May 29, 2020, then followed at 6 months and 12 months (58% of the 2469 people discharged from the hospital completed the 6- and 12-month follow-up visits) 

-- mean age 59, 53% men, never smoker 82%/current smoker 7%/former smoker 11% , hypertension 36%/diabetes 15%/coronary heart disease 8% 

-- Covid-19 severity scale: hospitalization not requiring supplemental oxygen (scale 3) in 25%; hospitalization requiring supplemental oxygen (scale 4) in 68%; hospitalization requiring high flow oxygen by nasal cannula or nasal cannula oxygen  non-invasive mechanical ventilation (scale 5) in 7%; hospitalization requiring ECMO or IMV (scale 6) in 8% 

-- treatment during hospitalization: corticosteroids 24%, antivirals 55%, lopinavir/ritonavir 14%, arbidol 49%, antibiotics 77%, IVIG 20%, thymosin 16% 

-- length of hospital stay was 14 days, length of ICU stay 18 days 

-- median follow-up time after symptom onset was 185 days for the 6-month visit and 349 days for the 12-month visit 

--all received questionnaires for self-reported symptoms, including the modified British Medical Research Council dyspnea scale (mMRC), and health-related quality of life (HRQoL) measures that included the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L) and the EuroQol Visual Analog Scale (EQ-VAS). Also, physical exam, 6-minute walking distance (6MWD), and laboratory tests (including the levels of 27 cytokines)

    -- those who had had pulmonary function tests or high-resolution chest CT scan (HRCT) abnormalities at six months were given the corresponding tests of 12 months 

-- 1164 non-Covid community-dwelling adult  controls were matched for age, sex, and comorbidities 

-- primary outcomes were symptoms, modified British Medical Research Council (mMRC) dyspnea score, health-related quality of life (HRQoL) from the above two indices, and distance worked in six minutes (6MWD) 

-- and, lung function assessment, using multivariable adjusted logistic regression risk factors

 

Results: 

--  having at least one sequela symptom: decreased from 68% (831/1227) at 6 months to 49% (620/1272) at 12 months, p<0.001 

    -- the 68% of Covid patients who had at least one post-covid symptom at 6 months was significantly higher than the 33% of controls (383/1164), p<0.0001

        -- each of the individual prevalent symptoms was significantly higher in those who had Covid versus controls, all with p<0.05; in particular there were more problems with mobility, pain or discomfort, and anxiety or depression 

    -- symptoms of dyspnea (mMRC score at least 1): increased slightly from 26% (313/1185) at six months to 30% (380/1271) at 12 months, p=0.014 

        -- these percentages were all significantly higher than in controls, p<0.05 

-- anxiety or depression: 23% (274/1187) at six months, increased to 26% (331/1271) at 12 months, p=0.015 

-- 6-minute walk (6MWD) less than the normal range: 14% (174/1254) at 6 months, decreasing to 12% (147/1284) at 12 months; though there was no difference in the median 6MWD scores 

 

--breakdown of sequelae by intensity of Covid infection: 

    -- any one of the symptoms (fatigue or muscle weakness was the most commonly reported symptom): 

        -- for scale 3: 69% at 6 months, 47% at 12 months 

        -- for scale 4: 66% at six months, 49% at 12 months

        -- for scale 5-6: 84% at six months and 52% at 12 months

        --the percentage of people with almost all of the sequelae increased as Covid infection increased

 

-- Lung function: 

    -- 349 patients completed pulmonary function tests, with 254 attending the 12-month visit 

        -- decreased lung diffusion capacity (carbon monoxide diffusion <80% of normal): no significant change from 6 to 12 months, with the following changes by Covid severity scale group at 12 months: 

            -- scale 3:23% (13/56) of patients 

            -- scale 4: 31% (36/117) of patients 

            -- scale 5/6: 54% (38/70) of patients 

        -- total lung capacity <80% of normal, in patients with scale 5/6 Covid severity group: at six months 39% (27/69) of patients, decreasing significantly 29% (20/70) of patients at 12 months, p=0.021 

    --those with abnormal lung HRCTs at 6 months had significant improvement at 12 months, depending on the severity of their Covid infections: scale 3 improved from being 100% abnormal to 39%, scale 4 (supplementary oxygen) from 100% to 40%, and scale 5-6 from 100% to 87% [no significant change in the latter group]

        --there was a significant correlation between finding ground-glass appearance and irregular lines on the HRCT and diffusion abnormalities on PFTs 

 

-- women versus men: 

    -- fatigue or muscle weakness: odds ratio 1.43 (1.04-1.96) 

    -- anxiety or depression: OR 2.00 (1.48-2.9) 

    -- lung diffusion impairment by PFTs: OR 2.97 (1.50-5.88) 

 

--return to work: of the 479 who had jobs prior to Covid, 422 (88%) had returned to their original work by 12 months, and 321 of these 422 (76%) returned to their level of work before Covid; those unable to return to prior work level was mostly from decreased physical functioning or unwillingness to do their prior work 

 

-- those on corticosteroids in acute Covid:  increased fatigue or muscle weakness, OR 1.51 (1.05-2.16)

-- those on IV immunoglobulin: decreased risk of fatigue of muscle weakness, OR 0.65 (043-0.98)

        --[though these might be select groups of sicker people?? more politically prominent people??] 

-- cytokine analysis (73 patients), collected during acute infection, then at 6 and 12 months later: both pro- and anti-inflammatory cytokines decreased over time, though those with greater reduction of IL-2, IL-5, IL-7, IL-12, and G-CSF had lower risk of lung HRCT abnormalities at 12 months 

 

Commentary: 

--though there was some significant recovery overall from 6 months to 12 months after severe infection, still almost ½ the people had at least one sequela from the infection. And the findings of dyspnea and anxiety/depression seemed to increase so that >25% had continued symptoms (and many had irreversible lung changes on HRCT). These numbers were from those with severe infection leading to hospitalization, a small minority of those with Covid infections. But the absolute magnitude of those severely infected, in the setting of 231,301,012 reported cases and 4,740,781 deaths as of 9/23/21 (see https://www.worldometers.info/coronavirus/ , which undoubtedly understates the real numbers), does translate to lots and lots of people who might have these long-term sequelae 

-- Covid-infected patients had more use of bronchodilators, antitussives, expectorants, antidepressants and anxiolytics after their covid infection, presumably reflecting the intensity of their respiratory and psych symptoms 

--though the majority of those working did return to work after a year, and a majority were able to return to their prior work/workload, there was still a significant group unable to do so (12% did not return to work, and 24% who did were not able to return to their prior level of work). Which is really pretty different from most other respiratory viruses (ie, covid really is bad….). and if generalized globally would mean huge numbers of people unable to return to work....

 

--there were interesting parallels to the original SARS epidemic in 2003, caused by SARS-CoV-1: 

    --one study found that there was lower health status of survivors up to 2 years after their initial infection

    --another found fatigue reported 4 years later 

    --fatigue and muscle weakness at 12 months after infection was most commonly reported in women and those given steroids in the acute illness [so, steroids were associated with more fatigue/muscle weakness with both SARS studies (old and new coronaviruses), but, again, was there a selection bias as to which patients got the steroids?]

    --the fatigue/muscle weakness was felt to be likely related to some combo of impaired lung diffusion capacity, viral-induced myocarditis, cytokine disturbances, muscle wasting/deconditioning, and steroid-induced myopathy 

--SARS patients had a high prevalence of lung diffusion impairment at 12 months (in patients with varying degrees of SARS infection severity), and this was associated with lung structural abnormality; the lung diffusion abnormalities in some persisted for years 

 

-- another study just came out on the prevalence of Covid-19 symptoms 7 months after mild Covid-19 infection in Geneva (see covid symptoms 7 months later AIM2021 in dropbox, or doi:10.7326/M21-0878), with 410 symptomatic outpatients who were interviewed at baseline and 7-9 months after the covid diagnosis, finding:

    --39% reported residual symptoms:

        -- fatigue: 21%

        -- loss of taste or smell: 17%

        -- dyspnea: 12%

        -- headache: 10%

    --[ie, lots of longer term symptoms in those with mild Covid infections]

 

Limitations of the above Chinese study: 

-- both the uniform Chinese population and the experience from only one hospital limits generalizability more broadly 

-- only about half of the discharged patients completed the followup. Was there a bias in who decided to return for the study? were those with longer term sequelae more likely to say “yes” to participating in the study? 

-- no info about the health status of the covid patients prior to developing covid 

-- these numbers reflect the long-term sequelae of Covid-19 in those with severe infections. We know from other studies that those with mild and even asymptomatic infections are at risk for "long covid" (see http://gmodestmedblogs.blogspot.com/2021/08/covid-long-covid-update-including-in.html ; and http://gmodestmedblogs.blogspot.com/2021/06/covid-long-term-sequelae-in-large-va.html ) . and there was the 7-month study cited above finding longer lasting sequelae in those with mild infections. seems like there is probably a gradient of risk of sequelae: those with more severe infections have more long-term problems, though those with mild (or even asymptomatic) infections are not necessarily spared...

-- one question overall in terms of long Covid is how much of the symptomatology was somaticization related to just having had Covid, and perhaps the associated fears of the unknown??  

    -- we have seen somatic symptoms ascribed to other medical conditions, such as chronic Lyme disease, or PANDA syndrome, where these symptoms were likely unrelated to Lyme or strep infections. and, for an extensive list of "mass hysteria outbreaks", where lots of people had somatic symptoms attributed to psychologic trauma, etc, see https://en.wikipedia.org/wiki/List_of_mass_hysteria_cases 

        -- it is clear that long-term sequelae associated with covid-19 are higher than with other respiratory infections such as influenza. However Covid might elicit more of an anxiety response (as is pretty clear) and perhaps more somatic symptoms?? Does this anxiety translate into higher a response rate vs in control patients on the questionnaire?

    -- but there are some issues that further the likelihood that the "long covid" is not simply "psychosomatic": 

        -- the consistency of results in all of the studies, where fatigue is really common and pre-eminent in all that i have seen

        -- some of the symptoms very likely reflect underlying cellular pathology, such as smell disorders and taste disorders being associated with viral involvement in the central nervous system, or dyspnea associated with abnormal CT scans and pulmonary function tests

        -- also, the 6-minute distance walked (abnormal in 14% post-covid) was really not so impaired post-infection (much less so than fatigue/muscle weakness, found in 22% of covid pateints vs 6% of controls) and did not change significantly over time. one might think that largely psychological symptoms might be reflected in more evident problems like walking for 6 minutes on a level surface??? (ie, i would think there would be more consistency in all of the impairments if the symptoms were not physiologic). they did not perform the 6MWD in the controls, so hard to assess more rigorously

    -- that all being said, the relationship between "physiologic" and "somatic" symptoms is complex. everything is ultimately physiologic, with the brain recording a somatic symptom such as "pain" as "painful" whether from a broken bone or stress. And, in either case, these are both clinical conditions that need support from us and appropriate therapies. and not be written-off as non-significant

 

So, all of this reinforces that Covid-19 is not just a potentially fatal viral infection, but that the long-term burden of disabilities from infection is/ will be likely gigantic. This means that we clinicians should inquire about residual symptoms after Covid-19 infection and validate/attend to them, especially since patients may be hesitant to bring them up spontaneously

 

And, this just continues to reinforce the imperative for vaccination, and that this must be done on a global basis to prevent ongoing infections as well as continuing development of progressively worse and potentially vaccine-resistant mutations. and also the importance of mask-wearing and other mitigation strategies to decrease Covid as well as the slew of other respiratory viruses about the descend on us (flu, rsv, paraflu, adenoviruses, rhinoviruses, etc etc)

 

geoff

 

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