long covid: long-term pathology

 this is the second blog on long covid, highlighting a couple of studies documenting long-term pathologic organ abnormalities in some individuals with long covid, and these abnormalities may explain some of their long-term symptoms: see https://journals.sagepub.com/doi/epub/10.1177/01410768231154703, or covid long covid organ impairment JRoyalAcadMed 2023 in dropbox)

 

Details:

-- 536 individuals in a UK study who had recovered form acute covid infection but had long covid symptoms 6 and 12 months after their initial infection

-- mean age 45, 73% female, 89% white, 32% health care workers, 13% having had acute Covid hospitalization (ie mostly mild-moderate cases)

-- BMI 25, smoking never 65%/current 3%/past 32%; hypertension 10%; diabetes 2%; heart disease 1%; asthma 19%

-- organ assessment was by 40-minute MRI scans, blood work or other incidental findings; all assessed both initially and at 6 month follow-up

    -- MRI targeted 49 organ-specific metrics, focusing specifically on the lungs, liver, heart, kidneys, pancreas and spleen (but not the brain)

-- 92 healthy controls matched for age and sex but without prior covid or hospitalization in the past 4 months. these controls also received follow-up MRIs

-- long covid was defined as symptoms lasting for at least 12 weeks

-- 55% of long covid patients had acute covid that was confirmed by antibody or PCR

 

-- primary objectives:

    -- symptoms, organ impairment and function over 1 year, and specifically assessing ongoing breathlessness, cognitive dysfunction, and quality of life

    -- association between symptoms and organ impairment

--median time from acute infection to further assessment was 182 days

 

Results: 

-- 331 (62%) who had organ impairment or incidental findings had follow-up

    -- mean number of symptoms: 10 at 3 months and 6 at 12 months, a significant decrease (a bit confusing, since they write 3 symptoms at 12 months later in the article)

        -- the symptoms that decreased the most: systemic symptoms (fever, myalgia, joint pain, fatigue, headaches) decreased from 48% at baseline to 1% at 1 year, and cardiopulmonary ones (from 43% to 5%). fatigue, breathlessness and cognitive dysfunction remained high at 1 year (see top graph below)

        -- 60 people (18%) had complete symptom resolution at 1 year

-- common symptoms at 6 and 12 months, respectively:

    -- extreme breathlessness: 38% at 6 months and 30% at one year

    -- cognitive dysfunction: 48% and 38%

    -- fatigue: decreased from 98% to 64%, a significant improvement, but still the most common symptom at follow-up 

    -- poor health-related quality of life (EQ-5D-5L <0.7): 57% and 45%

        -- all of these outcomes were more common in women, younger participants, and those with single-organ impairment. and this group was more likely to have at least one symptom

            -- EQ-5D-5L: a scale measuring the five dimensions of mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; and the 5 limitations of no problems, slight problems, moderate problems, severe problems and extreme problems

 

-- MRI findings:

    -- liver: steatosis in 38% and hepatomegaly in 10%, each at baseline and at follow-up in 1 year

    -- pancreas: high fat in 25% at baseline and follow-up

    -- kidney: larger volume in 10%, which increased a bit in follow-up (statistically significant on the left kidney but not right)

    -- all of these findings were much lower in the healthy controls (see second graph below)

 

-- Laboratory findings (these were buried in the supplementary materials, which can be found at https://journals.sagepub.com/doi/10.1177/01410768231154703#supplementary-materials ). reporting only the notable numbers >10%

    -- ALT high in 16% at baseline and 14% on follow-up

    -- AST high in 9% at baseline and 12% on follow-up

    -- ESR high in 11% at baseline and 9% on follow-up

    -- potassium high in 48% at baseline and 37% on follow-up

    -- no information on the healthy controls

 

-- function over 1 year:

    -- at baseline, health quality of life was poor, especially for problems completing usual activities of living (56%) and pain (45%), reporting moderate to extreme difficulties

    -- at follow-up, 28% still complained for severe breathlessness; 90% had taken covid-related time off work (median 125 days); 95% of healthcare workers had taken time off work (median 180 days, and 63% had taken >100 days)

    -- single-organ impairment did improve from 69% to 59% of participants, but clearly remained high

    -- multi-organ impairment did not improve (nonsignificant decrease from 29% to 27%)

        -- those with lung impairment as well as those with impairment in at least 3 organs had the highest symptom burden

    -- in the 60 patients with no symptoms at follow-up: organ impairment was present in 72% at baseline and 62% at follow-up

    -- in the 264 symptomatic people, 32% were without organ impairment at baseline and 42% at follow-up

 

-- association between symptoms and organ impairment:

    -- neither abnormal lab tests nor organ impairment were predictive of full symptom resolution at follow-up

    -- there was a significant relationship between liver fat on MRI and symptoms of breathlessness

    -- higher liver volume/hepatomegaly at follow-up was associated with poor quality of life

    -- myocardial injury: 9% at baseline increasing to 18% at follow-up; low LVEF in 6%, stable from baseline to follow-up

 

-- single and multi-organ impairment (again, the article was not totally consistent in these numbers):

    -- baseline: 69% single-organ, 23% multi-organ

    -- follow-up: 59% single-organ and 27% multi-organ

 

 

 

HC= the 92 healthy controls, whole cohort = all 536 patients evaluated, follow-up cohort = the 331 who had both baseline and follow-up evaluations

 

Commentary:

-- several studies have documented long covid symptoms far out from the initial infection, eg see 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

-- a UK study also found that referrals to specialists post-covid were similar in those who were not hospitalized (mild-moderate infections) vs hospitalized (severe), and the former were even more likely to have shortness of breath or fatigue, and reduced quality of life

-- in a US study of 273,618 covid survivors, long covid was found in 37% of the individuals 3-6 months post acute infection; symptoms were abnormal breathing in 8%, chest pain 6%, headache 5%, abdominal symptoms 8%, cognitive symptoms 4%, anxiety/depression in 15%: see https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003773

-- and the last long covid study from earlier this week: http://gmodestmedblogs.blogspot.com/2023/04/long-covid-large-review-of-risk-factors.html , found that in huge numbers of people, there was a significantly higher rate of long covid by an array of different risk factors

 

-- this current study of largely non-hospitalized patients with long covid found:

    -- multi-organ impairment at 6 and 12 months in 29%

       -- there was actually an increase in multi-organ involvement at followup (though only a little), but this is consistent with prior studies finding that long covid symptoms can start well after an acute infection

    -- some association between organ impairment and symptoms, though not sufficient evidence to evaluate any long covid subtypes

    -- there was no relationship between blood biomarkers and clinical presentation

    -- symptoms, blood tests and multi-organ MRI did not predict the trajectory or recovery of long covid

    -- 3 in 5 people with long covid had impairment in at least 1 organ, 1 in 4 with impairment in more.

    -- quality of life in those with long covid was remarkably decreased (as found in prior studies), including healthcare workers having decreased ability to work (very few had a prior history of diabetes or heart disease); 19 of the 172 healthcare workers  had symptoms at follow-up and were off work a median of 180 days

-- the relationship between NAFLD/diabetes and covid outcomes has been pretty clear since the beginning of covid. this study confirmed a relationship between markers of liver dysfunction and increased risk of symptoms in women and those who have obesity (as has also been found in other studies)

-- a few other long covid blogs of note:

    --http://gmodestmedblogs.blogspot.com/2022/10/covid-long-covid-less-common-with.html: long covid seems to be less common with omicron. not sure if that is from an inherent difference in the variants, or the timing of evaluation, since omicron occurred after lots of people had had covid (perhaps a few times) and vaccines, and both of these might have decreased long covid

    -- http://gmodestmedblogs.blogspot.com/2022/05/covid-keeps-on-getting-longer.html: a Chinese study assessing long covid 2 years later (the longest study to date), finding that the proportion of people with at least one covid symptom was 68% at 6 months, 49% at 12 months, and 55% at 2 years

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

 

-- another recent study of 144 covid pneumonia patients in China found that 2 years later, CT scans showed that 23% still had fibrotic interstitial lung disease (ILD) and 16% nonfibrotic (both with decreased diffusion capacity), though the incidence of ILD did decrease a bit over time (42% at 6 months, 42% at 12 months and 39% at 2 years). overall 14% still had dyspnea on exertion, though those with fibrotic ILD on CT were more symptomatic  (see covid chest CT abnl Radiol2023 in dropbox, or https://pubs.rsna.org/doi/10.1148/radiol.222888 )

-- and a study 2 years ago from the UK Biobank found that there were significant changes in brain MRIs in patients who had had pre-covid MRIs, then had mild covid, and then repeat MRIs 131 days later: see http://gmodestmedblogs.blogspot.com/2021/06/covid-really-scary-brain-changes-in.html 

 

    -- UK: in the UK's large long covid clinic, non-hospitalized patients received specialty referrals for their symptoms at the same rate as those who were hospitalized, and were actually more likely to have symptoms of fatigue, breathlessness, cognitive dysfunction, and reduced quality of life

-- the issue of more symptoms in women has sometimes been written off as "women have more vague symptoms overall, such as with fibromyalgia...", and several of the symptoms are nonspecific

    -- this study and the Chinese one clearly undercut that (sexist) interpretation, with documented "pathology" on MRI or CT. Though, i might add, even if these symptoms reflected an underlying depression, that can certainly be at least as debilitiating as specific organ pathology

    -- for some physiologic reasons that women may have more long covid, see http://gmodestmedblogs.blogspot.com/2023/04/long-covid-large-review-of-risk-factors.html

 

Limitations:

-- we do not have information on a baseline, pre-covid MRI in these with long covid. were the findings just incidental ones that predated covid and had nothing to do with a covid infection? we know that MRIs pick up lots of stuff (and not infrequently too much information: eg a systematic review of back MRIs in people who never had symptomatic back pain found that 29-43% had disc protrusion as well as annular fissure in 19%-29%, both increased with age (see lbp mri ct in normals AJNR2014 in dropbox, or doi.org/10.3174/ajnr.A4173, and see more details in http://gmodestmedblogs.blogspot.com/2016/10/radiologist-variability-in-mammography.html)

    -- they did compare the MRI findings to healthy controls vs long covid patients and found a pretty big difference (see graph above), but there were only 92 controls, and they only controlled for age and sex. not as good as having patients be their own controls (ie having pre-covid MRIs and then post covid ones, as in the UK Biobank study mentioned above).....   so, potential limitation of the findings above

    -- patients with normal assessment at baseline were not followed in this study. and this may reflect a couple of concerns: there was a clear selection bias of those followed, making generalizing the results less clear; and there are some people who have normal baseline function after covid but then develop long covid later (or even develop long covid after initial asymptomatic infection)

-- this study assessed the "UK first wave" of covid (Jan to Sept 2020) with 497 people (though 39 people were 'second wave', after Sept 2020), limiting generalizability to other more current covid variants. And of course there is that structural deficiency in assessing long covid: important results take many months post-infection to be assessed. and by then we likely have been through several subsequent variants.

-- many patients did not have antibody- or PCR-confirmed covid infection, likely because it was early on in the pandemic and many were not so sick; but at that time covid was rampant, so the pre-test probability of having had covid was really high

-- not clear that their results are generalizable to other areas: eg patients who had more than mild covid infections, other countries, or even within different areas in the UK. this was a select group of patients who responded to an advertisement or had specialist referral for imaging.

-- no brain MRI done to see if pathologic changes tracked with cognitive impairment

    -- and even mild covid is associated with pretty profound changes in brain imaging: see covid brain changes JAMA2022 in dropbox, or doi:10.1001/jama.2022.4507, as well as http://gmodestmedblogs.blogspot.com/2021/06/covid-really-scary-brain-changes-in.html 

-- the lab tests were reported as binary ("high" was just above their normal limits, so an ALT elevation of 36 U/L in a woman was reported as just as abnormal as one of 336 U/L ), which really limits the interpretation

    -- also when reporting that ALT was high in 16% at baseline then 14% at followup raises other questions: were these the same people with inflammation leading to "high" ALT? if in the same person, did the number increase or decrease, and by how much?

 

so we have learned a few things about covid, which i think are important for the future as covid becomes endemic:

-- covid can lead to long-term symptoms and these symptoms can be associated with severe and apparently permanent organ dysfunction

-- vaccination dramatically decreases the likelihood of long covid, as per prior blogs. and at this point vaccination should be strongly reinforced

-- as covid becomes a regular recurrent virus, we should not consider it just another virus in the soup of viral respiratory viruses. covid is not just another flu....

-- and we clinicians and public health officials should, i think: 

    -- try to undercut the mis-messaging around that covid is really not so bad, that it is just another virus, that vaccines don't really matter, that it is really nothing to worry about....

    -- be extra persistent in educating people of the importance of mitigation strategies (eg wearing masks especially at times when covid cases increase or wastewater assessments suggest an uptick in cases within the next few weeks)

        -- and, try to convince people that masks are important for covid prevention, despite the (pretty terrible) Cochrane review: http://gmodestmedblogs.blogspot.com/2023/02/cochrane-review-critique-dont-get-rid.html

    -- try to impress upon people that vaccinations are and will continue to be an important preventative measure (even though many people seem to think that  "i've already gotten 4 of them, and they hurt/cause side effects, and i am done thinking about covid...."

geoff

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