Covid: post-covid syndrome

 The New York Times had a long but intriguing article on the post-Covid syndrome (see https://www.nytimes.com/2021/01/21/magazine/covid-aftereffects.html?referringSource=articleShare ), making several strong points:

-- many patients from diverse backgrounds (including doctors and nurses) develop long-standing symptoms after Covid infection (“long haulers”, or "long Covid"), with many individuals profiled in this article

-- Mount Sinai Hospital in New York developed its Center for Post-Covid Care last May, now with more than 1600 patients

-- patients experience a diverse set of symptoms including fatigue, pain, shortness of breath, light sensitivity, exercise intolerance, insomnia, tachyarrhythmias, diarrhea/cramping, and memory problems/”brain fog”, with examples of people who cannot put a cogent sentence together, get trapped in their shower because they can’t remember how to get out, need to write themselves notes to remind themselves when to eat, unable to multi-task (eg, listen to music and fold laundry), ...

 -- for another recent blog on long-term sequelae, see http://gmodestmedblogs.blogspot.com/2021/01/covid-longer-term-sequelae-and-new.html , where 488 patients in Michigan were contacted 60 days after Covid-19 hospitalization, finding (among lots of other things) that 159 had cardiopulmonary symptoms (with 92 having new or worsening symptoms), and others with an array of disabilities and functional impairments (almost half not able to return to work)

    --other studies have found that many people with post-Covid syndrome have had only mild Covid-19 disease initially

-- prevalence of the post-covid syndrome is unclear, some estimating 10% of all Covid-19 patients. a study in Ireland found that more than half the patients had some symptoms 10 weeks later (and 1 in 3 did not return to work); another one at the Faroe Islands found that half the patients with mild Covid infections had at least one symptom 18 weeks later.

--And a study from China found that three quarters of the patients had at least one symptom 6 months later (see https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2932656-8 ): 1733 patients. most common symptoms were fatigue or muscle weakness in 63%, sleep difficulties in 26%, anxiety/depression 23%, and about 25% had a median 6-minute walking distance less than the lower limit of the normal range. In general SARS-CoV-2 blood antibody tests and mean titers of neutralizing antibodies were significantly lower than during the acute phase (ie, the symptoms were in the setting of waning immunity, not active infection with higher immune responses). And, notably, 107 of 822 people without acute kidney injury and normal eGFR had an eGFR <90 at follow-up

-- this post-Covid syndrome recalls other poorly identified or post-infectious disease syndromes, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), SARS, H1N1 influenza, Guillan-Barre syndrome, multiple sclerosis (presumably associated with Epstein-Barr infection), rheumatic fever, Lyme disease (and associated arthritis as well as "chronic Lyme disease"), PANS (pediatric acute-onset neuropsychiatric syndrome), Q fever,...

    -- and there is some measurable immunologic dysregulation in some of these conditions, including prolonged inflammatory states after exercise, sympathetic nervous system dysregulation, decreased activity of natural killer cells in those with ME/CFS

    -- there is also interesting research suggesting that in ME/CFS is associated with changes in microglia in the brain that might profoundly affect neural function [there are lots of studies showing that the microglia around neurons do much more than providing structural scaffolding for the neurons but also interact with neurons electrically and biochemically, significantly modulating neural function. And there is even current research in chronic pain management targeting microglia. and, perhaps notably, Einstein donated his brain to science, and on analysis, the numbers of neurons/connections were not much different from us mere mortals, but the number of glial cells was dramatically more. an interesting book on this was "The Other Brain" by R Douglas Fields]

-- they speculate that women tend to have a stronger T cell response to SARS-CoV-2 (for example, testosterone has some immunosuppressant activity), which might explain the higher rate of post-Covid syndrome found in women

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an article noted in the NY Times above looked at the autoantibody response to Covid-19 infection (see https://www.medrxiv.org/content/10.1101/2020.12.10.20247205v4 , covid autoantibody response medrxiv2021 in dropbox, or doi.org/10.1101/2020.12.10.20247205)

-- 194 Covid patients were screened by Rapid Extracellular Antigen Profiling (REAP) for autoimmune antibodies against 2770 human extracellular proteins, finding high autoantibody levels against immunomodulatory proteins including against cytokines, chemokines, complement components, and cell surface proteins. These autoantibodies in the previously infected Covid-19 patients target proteins involved in acute phase response, type II immunity, leukocyte trafficking, interferon responses, and lymphocyte function/activation

-- these antibodies were quite common: 84% of samples that were ELISA-positive against the SARS-Cov-2 receptor binding domain (RBD) had some autoimmune abnormalities vs 0% in those who were ELISA-negative

-- these autoantibodies inhibit immune receptor signaling and alter peripheral immune cell composition

-- animal studies suggest that these autoantibodies exacerbate severe disease in the mouse model of SARS-CoV-2 infection

-- other reports have identified pathological B cell populations in Covid-19 patients, similar to those found in patients with lupus and other autoimmune diseases (ANA, anti-IgG rheumatoid factor, antiphospholipid antibodies, and antibodies against type I interferons (IFN-1)

    -- of note, the number of autoantibody reactivities were at a very high level, greater than those found in patients with lupus

-- there is evidence that neutralizing antibodies against IFN-1 may antagonize innate anti-viral response in those with Covid-19

-- the number of autoantibody reactivities by REAP increased with Covid-19 disease severity

-- though they could not ascertain REAP values prior to these people getting Covid-19 (no pre-infection serum available), the time course and extent of positivity (eg increasing from low levels to very high levels over time) suggest newly acquired antibodies

--so, bottom line from this preprint, pre-peer reviewed article is that there is a huge array of autoantibody reactivities, suggesting functional humoral immunopathology as a component of Covid-19 infection. But none of these autoantibodies were Covid-specific, though many of these autoantibodies (e.g. anti-IFN-1) had an uncommonly high prevalence. And, further, these perturbed biological pathways created by these autoantibodies, could lead to Covid-associated pathophysiology (for example, some of these autoantibodies were directed against inflammatory markers such as ferritin, CRP, and lactate, all found at higher levels in those with worse Covid infections): as the authors put it, “many tissue autoantibody bodies were present across the diverse physiological compartments frequently implicated during post-Covid syndrome”

-- there are also suggestive data pointing to a potential autoimmune response to ME/CFS, including a study showing benefit from cyclophosphamide (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201056/).  Will dexamethasone help prevent the development of Covid long haulers by being immunomodulatory (nipping an aberrant immunologic response in the bud?)

So, an impressive article in the New York Times, backed up with several medical studies, documenting that the effects of Covid-19 extend well beyond mortality, the frequently measured/reported marker. Perhaps as a result of immune dysfunction and the creation of a slew of autoantibodies. For many patients, these longer-term effects may be fundamentally life-changing and, though some do seem to improve over time, at this point many do seem to last extended periods of time. And, in some cases, the post-viral sequelae are worse than the initial infection.  I think this is an important talking-point with patients who are reluctant to get the vaccine.  it is not just hospitalization and the associated mortality that counts...... And bad outcomes happen to younger folks.

 

And, it is incumbent on us clinicians to understand the breadth of these long-term effects, and not simply write them off as  “psych issues”: many clinicians over the years have written off chronic fatigue or chronic lyme or chronic EBV...  And, i think we are more prone to doing this since we do not fully understand either the pathophysiology or appropriate therapies (as has happened with ME/CFS over the past 25 years). 

    --by the way, there are many studies suggesting that depression is associated with chronic inflammation ....  (eg, see http://gmodestmedblogs.blogspot.com/2019/10/healthy-dietantiinflammatories-dec.html ). and depression is one of the relatively common findings with many of these chronic post-infectious syndromes

geoff

 

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