long covid: large review of risk factors; importance of continued vaccines

 

i think that most of us are suffering from covid fatigue, including myself.  but after 257 (!!!) blogs on covid, i will indulge yet another time or 2, given a couple of important articles on long covid: this one a large meta-analysis of many smaller studies, helping to clarify the sometimes conflicting conclusions about risk factors for long covid. The next blog later this week will review studies showing significant long-term pathological organ impairment by SARS-CoV-2 virus. For the current article, see covid risk factors for long covid JAMA2023 in dropbox, or doi:10.1001/jamainternmed.2023.0750 

  

Details: 

-- 41 articles were found documenting predictors of long covid (they used the WHO term: post-covid condition, PCC), in individuals at least 18yo 

    -- 30 were rated as “high quality” and 11 as ”moderate quality” 

    -- 860,783 patients were included 

-- all studies had follow-up of at least 3 months postinfection; most were longer, up to 1 year 

-- most were interviews or questionnaires, but many were clinical assessment 

  

Results: 

-- risk factors identified, with odds ratio that the risk factor is associated with long covid: 

    -- female sex: 38 studies with 727,630 patients, odds ratio 1.56 (1.41-1.73) 

    -- age: 9 studies with 324,950 patients, OR 1.21 (1.11-1.33) 

    -- high BMI: 16 studies with 710,807 patients, OR 1.15 (1.08-1.23) 

    -- smoking: 20 studies with 455,204 patients, OR 1.10 (1.07-1.13) 

    -- comorbidities, overall:  34 studies, OR 2.48 (1.97-3.13); with breakdown: 

        -- anxiety and/or depression: 4 studies with 634,734 patients, OR 1.19 (1.02-1.40) 

        -- asthma: 13 studies with 639,397 patients, OR 1.24 (1.15-1.35) 

        -- chronic kidney disease: 8 studies with 255,791 patients, OR 1.12 (0.98-1.28) 

        -- COPD: 10 studies with 257,340 patients, OR 1.38 (1.08-1.78) 

        -- diabetes: 18 studies with 259,978 patients, OR 1.06 (1.03-1.09) 

        -- immunosuppression: 3 studies with 967 patients, OR 1.50 (1.05-2.15) 

        -- asthma: 13 studies with 639,397 patients, OR 1.24 (1.15-1.35) 

        -- ischemic heart disease: 5 studies with 201,906 patients, OR 1.28 (1.19-1.38) 

        -- previous hospitalization or ICU admission: 8 studies with 265,466 patients, OR 2.37 (2.18-2.56) 

        -- vaccination with 2 doses of vaccine: 4 studies with 249,788 patients, finding vaccination is associated with half the risk of long covid: OR 0.57 (0.43-0.76) 

  

Commentary: 

-- as mentioned in prior blogs, SARS-CoV-2 is not unique with having the long covid syndrome. Prior similar viruses (those causing the outbreaks of SARS 20 years ago and MERS 10 years ago) had been associated with long-term post-infectious sequelas. SARS infection was associated with some  long-term symptoms 4 years later, after which i could find no further assessment…  

 

-- this current huge meta-analysis of diverse studies found many associations between long covid, up to 1 year after acute infection, implicating many of the known risk factors, and lending credence to the many individual studies that have emerged over the last 2 years 

-- of note, female sex, older age, higher BMI and smoking were strongly associated with long covid, as well as many of the pre-existing comorbidities and severity of the acute covid infection 

 

-- and, why, you might ask, are women more affected by long covid???  

-- there are several potential explanations that might explain physiologically why women have been shown consistently to having a higher risk of long covid, perhaps attributable to women having a different immunologic response than men: 

    -- there may be direct hormonal effects on the immune response: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119719/ 

    -- women have higher acute phase reactions with higher IgG antibody responses to SARS-CoV-2: see A comparison study of SARS‐CoV‐2 IgG antibody between male and female COVID‐19 patients: A possible reason underlying different outcome between sex - Zeng - 2020 - Journal of Medical Virology - Wiley Online Library 

    -- also, the ACE-2 gene (which binds SARS-CoV-2 on the spike protein) is on the X chromosome, which could be part of the reason for the sex differences: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337796/, and for a more extensive biological explanation:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287119/ 

    --so, there are some combinations of immunological differences between women and men that could be part of the explanation as to why men are more likely to get severe acute covid infections yet women more likely to have long covid (and women are much more likely to get immunological diseases such as lupus, rheumatoid arthritis, etc) 

 

-- several of the more recent long covid studies reflect the more current situation in terms of covid variants: 

    -- a preliminary UK study comparing long covid during delta vs omicron variants found omicron to be less likely to lead to long covid: see http://gmodestmedblogs.blogspot.com/2022/10/covid-long-covid-less-common-with.html (though, see below in limitations) 

    -- an Italian study found that vaccination decreased long covid: see http://gmodestmedblogs.blogspot.com/2022/07/covid-long-covid-decreased-with.html 

 

Limitations of this study: 

-- as with other meta-analyses, this one is combining studies of different patients in different countries with different social conditions with different comorbidities, etc.  These types of meta-analyses do add to our understanding by dramatically increasing the numbers of patients from the smaller studies and increasing the statistical power of the associations.  And when the meta-analyses find results that are confirmatory of those of the smaller studies, that is pretty powerful. But we still need to be cautious in just accepting the results uncritically 

-- the findings of risk factors is based on observational studies, which limit our ability to draw causal conclusions and allow us to find only associations. There might have been unmeasured variables that actually were causal. For example, we do know that diet and exercise affect the health of the immune system, but these were not analyzed

-- a related issue is that the studies were focused on coning down the assessment to individual risk factors. What about the risk for women having covid who have diabetes, perhaps also with some chronic kidney disease??? Does the combination increase long covid risk arithmetically? Geometrically? Do some combinations actually decrease the risk? This is rather important since many of our patients do not have just a single risk factor…. And many of the risk factors in different studies had binary cutpoints (eg BMI >30 vs <30). But there is quite likely a large difference in outcome between those with BMI of 29.6 vs 45.7.

-- one particular issue here is timing. These studies were done at very different times, when covid variants were different (though most of them were early on, and not reflecting the newer variants, for which we have not waited long enough to get long-term results about long covid), people may have had different vaccines with different efficacies, may have had immunologic boosting from prior covid infections, may have been exposed to very different treatment approaches, etc.  All of this may limit generalizability to current situations in different countries (or even different parts of the same countries…), and may affect our ability to generalize the results to areas with different covid epidemiology 

 

So,  the importance of this study is several-fold: 

    -- it is important to understand that  even small increases in odds ratios for the above noted risk factors translates to huge numbers of people getting long covid  (the WHO’s current estimate is 761,402,282 confirmed covid cases as of 16March2023, with 6,887,000 deaths: https://covid19.who.int/, so even a few percent increase in long covid means lots and lots of people!!!!)

    -- we need to have systems now to provide care for these huge numbers of long covid individuals. And this issue is global and needs a global solution, with the resource-rich countries taking a leading role 

    -- we need to plan future resources to meet the future cases, as SARS-CoV-2 continues to morph into new variants (typically increasingly communicable) and subsequent covid iterations achieve endemicity. And newer variants could potentially lead to more long covid

     -- and, though there seems to be increasing popular resistance to yet another Covid vaccine, it does seem that vaccination has been and is likely to continue to be an important part of decreasing the risk of long-covid, which can be a life-changing disabling consequence of this miserable virus. A few more comments on vaccination 

        -- 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 vaccination mandates may well be necessary, just as they are for kids going school: interestingly, several of the southern states which seem to be covid mandate averse (and attacking them), such as Mississippi which "requires" DTap, polio, hepatitis B, MMR, and varicella vaccine in all kids from pre-kindergarten through 12^th grade, per https://msdh.ms.gov/page/14,8569,71.html ...... 

       -- and, Florida, the home of DeSantis and other anti-mandate demagogues, requires all that Mississippi does, but adds HIB and PCV vaccines to the mix as "required" for school 

 

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

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

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

            -- and, one thorn in our sides might be the Cochrane report that negates the utility of masks, a report that seems to have gotten lots of popular attention even in the NY Times and  more legitimate press; but this is a study (I think) that is terribly done and basing their conclusion on a misreading of the only 2 background studies they cite: see 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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