long covid: some new insights

 3 articles were published recently that may shed some light into the enigma of “long covid”, now morphing into PACS, or Post-acute Covid-19 syndrome. the whole issue of PACS is quite unclear. These symptoms can occur in small or large percentages of those with Covid (varies a lot in the studies), frequently happen in those who have mild symptoms or even are asymptomatic, can start early in the covid course or after a several month delay, can happen in quite healthy young people with no particular comorbidities, can vary from mildly disabling (a bit of fatigue, hair falling out, small changes in smell/taste) to being pretty devastating (unable to function because of fatigue, brain fog, profound changes in taste making it hard to eat, even severe neuromuscular problems).  Will do one article today (too long for others), with follow-up blog on 2 others. 

  

The potential role of the GI microbiome in PACS/long covid (see covid long covid gut microbiome BMJ2022 in dropbox or doi. org/10. 1136/ gutjnl- 2021- 325989)  

  

Details:  

-- 106 patients in 3 different hospitals in Hong Kong were followed prospectively from hospital admission to 6 months later, along with 68 non-Covid as controls, between February 1 and August 31, 2020 (at that time pretty much everyone with Covid was admitted to the hospital) 

-- mean age 48, 53% female, 43% with at least one comorbidity: 17% hypertensive/15% type II diabetes  

-- Covid severity: 4% asymptomatic, 29% mild, 52% moderate, 9% severe, 6% critical   

-- antimicrobials during hospitalization: 53% lopinavir/ritonavir, 28% ribavirin, 37% interferon, 24% antibiotics  

-- these 106 patients had serial fecal microbiomes assessed

    -- 47 had stool samples at admission, 64 at one month, and 68 at six months  

-- PACS was defined as at least one persistent symptom at 4 weeks  

-- PACS was reported in 81% at 3 months and 76% at 6 months (33% with >3 symptoms)  

    -- at 6 months, most common symptoms were fatigue (31%), poor memory (28%), hair loss (22%), anxiety (21%), and difficulty sleeping (21%)  

        -- patients with or without PACS at 6 months: no significant differences in age, gender, comorbidities, use of antibiotics, or Covid disease severity  

   

Results:  

-- of the 68 patients with stool evaluation at 6 months, 74% had PACS  

-- antibiotic-naïve covid patients (both PACS and non-PACS) vs non-Covid controls:  gut microbiota composition and bacterial diversity was significantly lower in those with Covid than in non-Covid controls at 1 month.  

-- there was no significant difference at baseline or at 6 months whether the patients were on antibiotics or not during the covid admission  

    -- BUT, there was no information about the specifics of the antibiotics given (which ones and for how long), with different antibiotics having different degrees of microbiome toxicity 

   

--Covid patients developing PACS:  

    -- microbiome analysis at Covid admission:  decreased bacterial diversity and richness in those later developing PACS, with significant differences from those not developing PACS 

    -- bacterial species in those developing PACS: 28 species diminished and 14 enriched at both baseline and follow-up samples, with those subsequently developing PACS having:  

        -- higher levels of Ruminococcus gnavus, Bacteroides vulgatus  

        -- lower levels of  Bifidobacterim pseudocatenulatum, Faecalibacterium prausnitzii, Collinsella aerofaciens, and Blautia obeum 

--Relationship between gut microbiota composition and PACS symptoms at 6 months:  

    -- no relationship between medical treatment or disease severity in the hospital admission and gut microbiota composition  

    -- no difference in SARS-CoV-2 viral load in both stool and respiratory samples and the subsequent development of PACS  

 

    -- respiratory PACS symptoms (cough, sputum, nasal congestion, shortness of breath) were associated with opportunistic gut pathogens: Streptococcus anginosus, Streptococcus vestibularis, Streptococcus gordonii and Clostridium disporicum 

        -- also, a 6-minute walk test was decreased at 6 months, associated with Clostridium innocuum, Clostridium bolteae, but increased with Bifidobacterium pseudocatenulatum, Roseburia inulinivorans and Bacteroides ovatus  

    --neuropsych symptoms (headache, dizziness, loss of taste or smell, anxiety, difficulty sleeping, difficulty concentrating, sadness, poor memory, blurred vision) as well as fatigue were associated with nosocomial gut pathogens: Clostridium innocuum and Actinomyces naeslundii,  

    --derm (hair loss) associated with: butyrate-producing species Roseburia nulinivorans and Faecalibacterium prausnitzii  

    -- And, there was a large inverse relationship between PACS and bacterial species known to be beneficial to host immunity: Bifidobacterium pseudocatenulatum, F. prausnitzii, R. inulinivorans and Roseburia hominis

  

--Covid patients not developing PACS:  

    -- only 25 alterations of bacteria species 

        -- the gut microbiota of those not developing PACS was abnormal at 1 month, as compared to the non-Covid controls, but then reverted to normal at 6 months (and comparable to controls) 

        -- BUT in those developing PACS, their microbiome did not recover at 6 months and remained as it was at 1 month 

 

  

Commentary:  

-- up to three quarters of patients with Covid describe persistent symptoms at 6 months after Covid recovery  

-- other studies have found that gut dysbiosis (ie, abnormal microbiome) is associated with the severity of Covid infection and persistent disease after resolution  

    -- for example, one study last year similarly found that Covid infection was associated with major gut microbiota changes: much lower indices of gut microbiota richness, more so than in uninfected controls, with recovery of microbiota richness after the acute phase of illness. Of note those with the least gut microbiota richness had the highest CRP levels as well as the need for intensive care unit admission: see Six-month follow-up of gut microbiota richness in patients with COVID-19 | Gut (bmj.com) 

-- other studies have found that Covid is associated with other changes in the GI tract, including enhanced expression of ACE2 (the major binding site for SARS-CoV-2 virus)

-- neuropsychiatric findings with gut microbiome changes have been known for years (the “gut-brain axis”): see microbiome gut brain axis JClinInvest2015 in dropbox, or doi:10.1172/JCI76304), finding that the gut microbiome can affect emotional behavior, stress- and pain-modulation, and brain neurotransmitters   

-- the findings above relating gut microbiome changes with respiratory symptoms is consistent with older articles finding that in people with ARDS: the lung microbiome was enriched with gut-associated bacteria  (see Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome | Nature Microbiology ) 

    -- other studies have also found communication between the gut and lung microbiomes, including in the development of acute lung injury 

    -- for an old blog on the lung microbiome, see http://gmodestmedblogs.blogspot.com/2014/08/lung-microbiome.html 

  

--the above study has perhaps way too many specifics in the summary, but the main points of the study were:  

    -- PACS is largely found in people with mild to moderate Covid infections 

    -- there are specific early bacterial changes in the gut microbiome and the development of PACS later, including bacteria that produce more inflammatory cytokines and are less beneficial to host immunity. I did not include all of the microbiome changes in the summary above (see the article for the full details), but there are huge numbers of gut bacteria that have either pro- or anti-inflammatory effects 

    -- the abnormal microbiota in those with PACS persisted in the 6-month assessment, vs those without PACS where it reverted to normal, independent of the use of antibiotics in the Covid hospitalization 

    -- some of the microbial gut changes have known effects that might be involved in the development of PACS: F. prausnitzii is decreased in PACS and has immunomodulatory properties and can downregulate inflammatory responses by inhibiting the NF-kB pathway, decreasing IL-8 synthesis and secretion; it can also induce the anti-inflammatory IL-10; Blautia obeum had higher levels in those not developing PACS, has an anti-inflammatory effect; other Fermicutes bacteria regulate ACE2 expression 

    -- re-affirmation of many prior studies that there is communication between the microbiome in the gut and effects on the lung as well as brain. And in the case of the lung, there seems to be migration of gut bacteria into the lung microbiome 

  

-- the gut microbiome is disturbed in many chronic diseases (GI, inflammatory, metabolic, neurologic, and respiratory), and, for example those bacteria producing butyrate seem to protect against the negative effects of stress, including hair loss and anxiety. There was an interesting article finding that metformin increased the gut bacterium Akkermansia, and that Akkermansia in the absence of metformin enhanced glucose tolerance; or another finding that red meat caused microbiome changes leading the development of a chemical (TMAO) which causes huge increases in atherogenesis/CAD and heart failure (see http://gmodestmedblogs.blogspot.com/2014/10/heart-failure-microbiome.html ).  For many, many prior blogs of the microbiome, see http://gmodestmedblogs.blogspot.com/search?q=microbiome as well as lots of blogs on the role of antibiotics http://gmodestmedblogs.blogspot.com/search?q=antibiotic+overprescribing . these blogs also have studies on how much a healthy lifestyle (eating well, exercise, etc) improves/restores the health of the microbiome 

-- the pretty clear conclusion is that the composition of the various microbiomes both reflect external conditions (diet, exercise, stress, medications, chronic conditions) and seem to have effects on chronic symptoms, diseases, functionality 

 

--what are the implications of this microbiome study (assuming it can be replicated in a larger sample)? 

    -- for one thing, i have not seen any covid studies that look beyond the immediate comorbidities (obesity, diabetes, hypertension, etc). None i have seen have assessed the quality of the diet, the extent of regular exercise, the use of antibiotics, or other social issues which clearly affect the microbiome 

    -- of note, the basic diseases that are considered risk factors for severe covid infections all have pretty direct relationships with the microbiome: 

        -- obesity: BMI is a covid risk factor, and obesity itself is associated with microbiome changes: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333005/ . And, of course, obesity is related to diet, exercise, stress, depression, etc 

        -- diabetes: diabetes is associated with dysbiosis of the microbiome (eg see microbiome and diabetes WJD2020 in dropbox, or DOI: 10.4239/wjd.v11.i7.293). and also is associated with diet, exercise, BMI, etc 

        -- chronic diseases (liver, heart, kidney): many are related to the changes in the microbiome from our almost omnipresent societal risk factors associated with these conditions

        -- and other issues that affect the microbiome, which may also be related to covid outcomes: 

            -- smoking and the microbiome: see https://www.frontiersin.org/articles/10.3389/fphys.2021.673341/full

            -- alcohol and microbiome:  see https://pubmed.ncbi.nlm.nih.gov/26695747/ ) 

            -- other conditions associated with oxidant stress and inflammation (eg depression, rheum diseases, etc: eg see https://www.researchgate.net/profile/Gal-Winter/publication/322937907_Gut_microbiome_and_depression_What_we_know_and_what_we_need_to_know/links/5c5b83dd92851c48a9bfcaf4/Gut-microbiome-and-depression-What-we-know-and-what-we-need-to-know.pdf for depression; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685117/ for rheumatoid arthritis/autoimmune disorders)

    -- and, even the apparent increased covid in inner city communities may be explained by some of these microbiome changes: lack of access to healthy foods (either physical access to healthy foods or financial problems affording them), lack of safe venues for exercise, exposures to chemicals in the jobs, higher life stress levels, etc can affect the microbiome:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213601/ ) 

Limitations: 

-- Small sample size, so results should be replicated in a larger study 

-- unclear from this study what the actual mathematical predictive effect of gut microbiome at time of Covid with the subsequent development of PACS (ie, what is the real attributable risk of these microbiome changes??) And what specific changes confer higher risk of PACS??

--we do not have information about the pre-covid microbiome in those who later develop PACS. Though this study was impressive, it would have been good to know if the microbiome were normal prior to covid, changed dramatically with covid, and those changes were predictive of PACS.  Lots of things upset the microbiome, including antibiotics/medications, diet, exercise, many diseases (though sometimes the microbiome changes likely causes/aggravates some of the diseases…). Though this study did not find any difference in the baseline comorbidities they measured and did find that those who did not develop PACS had fewer changes in their first microbiome assessed and its resolution at 6 months. There is an NIH supported Human Microbiome Project which is compiling publicly available information into a database for future use. So, we may get more information on actual changes in the microbiome over time as more data accrues. Maybe in the future we will have a sufficient database to assess better the role of microbiome changes in subsequent development of biopsychosocial conditions 

    -- the above study is observational: unable to draw causal/etiological conclusions. Did the changes in the microbiome cause the prolonged covid symptoms (perhaps from sustained inflammatory response)? Were the microbiome changes just related to the underlying comorbidities (diabetes, obesity etc) and it is really just those comorbidities that are the problem? (after all, there was that study finding that adipose tissue is infected by SARS-CoV-2 and elicits an inflammatory response there (see covid obesity mechanism biomedrx2021 in dropbox, or doi: https://doi.org/10.1101/2021.10.24.465626)? If the latter were true, then focusing on changing the microbiome would be futile. But, especially in light of the frequent occurrence of PACS symptoms, it seems to be reasonably easy to construct a trial to see if changing the microbiome helps. Perhaps probiotics? Fecal transplant? Aggressively minimizing antibiotics? avoiding artificial sweeteners? These might help uncover the issue of causality 

-- the assessment of PACS symptoms was by questionnaire, which may not represent the true extent or quality of the symptoms 

-- there was minimal information on the use of antibiotics. Nothing on prior or subsequent use (only those used in the hospitalization for covid), and even then, no info on what antibiotics were given and for how long 

 

so, impressive study suggesting that the gut microbiome may be very important in the development of PACS/long covid. And perhaps may be responsible as well for severe covid infections, since these high-risk comorbidities are pretty much all associated with adverse microbiome changes. Which all suggests that a healthy microbiome may be important in preventing severe covid as well as PACS (as per above, some studies have found microbiome changes are associated with development of severe covid). a few points: 

--it is clear that developing a healthy microbiome is not easy: eg decreasing our other epidemic of obesity; curtailing antibiotic use for unclear indications, both in humans and animals; improving the quality of diet and amount of exercise.  

--but covid is here to stay, likely to become endemic and with spikes of new aggressive variants (ie we are in it for the long-term, with bumps in the road) 

--and, even though covid now seems to be migrating into a milder disease (which, of course, may not last), PACS is and has been predominantly in asymptomatic to mild/moderate cases 

--so, perhaps we need a paradigm shift. Vaccinations are clearly central to covid control, likely requiring newly engineered vaccines to target newer SARS-CoV-2 variants and also hit the virus at multiple epitopes. some newer medications also help lots in preventing severe disease (monoclonal antibodies, Paxlovid: see http://gmodestmedblogs.blogspot.com/2022/01/covid-merck-and-pfizer-pills.html, though no info on effect on PACS). But maybe we should be migrating more from a reactive mitigation strategy (masks, distancing, ventilation) toward a proactive microbiome-healthy approach (which will also improve many other chronic conditions)…

    -- this would take a concerted, systematic, well-funded public health initiative to improve these microbiome toxic issues (diet, weight loss, exercise, stress reduction, as above), with increased access for all of us to healthy inexpensive foods and other healthy behaviors that might be really beneficial (and even at much lower cost than what we have been going through), for covid as well as the myriad of other chronic diseases related to our unhealthy lifestyles/environment. but there needs to be a really concerted and coordinated public health effort to make these changes around the country, without public health being undermined by perverse political motivations... And, maybe the likely endemicity of covid will help push people forward, especially since PACS is so common and potentially devastating in younger people. and maybe this would decrease the recurrent necessity for those pesky masks.

geoff

 

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org

 

For access to the dropbox, go to link: https://www.dropbox.com/sh/0bmvtita8mzms11/XDTwHySFFg

Then go to "clinic", then to "clinical stuff" for articles, or go to https://www.dropbox.com/sh/nyle22q1fn6lkpk/AAB9B2hBj5Kw4gtrJAkI-UF8a?dl=0 for the powerpoint presentations

 

to get access to all of the blogs (2 options):

1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category​

3. or you can just click on the magnifying glass on top right, then  type in a name in the search box and get all the blogs with that name in them

 

or: go to https://www.bucommunitymedicine.org/ , a website from the Community Medicine section at Boston Medical Center.  This site does have a very searchable and accessible list of my blogs (though there have been a few that did not upload over the last year or two). but overall it is much easier to view blogs and displays more at a time.

 

 

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list