COVID: long covid longterm effects and physiology

 The New York Times just published a very impressive article about long Covid, citing several studies suggesting theories about some physiologic disturbances as well as their remarkably high incidence (see https://www.nytimes.com/2022/02/12/well/move/long-covid-exercise.html?referringSource=articleShare ).  Will review their article as well as several of the cited studies

 

Details:

-- as mentioned in several prior blogs, long Covid or PASC (Post-Acute Sequelae of Covid-19) is remarkably common. A biostatistician at Indiana University School of Medicine (Dr. Natalie Lambert) collected self-reported data from more than 1 million long Covid patients through the Survivor Corps, a Facebook support group for Covid survivors

-- one finding from this study, per Dr. Lambert, is that one of the most common symptoms is inability to exercise; patients get tired very easily and exercise seems to make it worse. Many clinicians have treated the inability to exercise as being from deconditioning, but, unlike the usual causes of deconditioning (prolonged bedrest, etc), exercise does not seem to improve it.

-- Another study of long Covid/PASC found that 89% reported “post exertional malaise”

    -- this study was an online survey of 3762 participants with confirmed or suspected Covid from 56 countries, with symptoms lasting over 28 days and onset before June 2020; they analyzed the presence of 203 symptoms in 10 organ systems (neuropsychiatric, systemic, reproductive, cardiovascular, musculoskeletal, immunological, HEENT, pulmonary, GI,  derm); 66 of the symptoms were tracked over 7 months (see https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/fulltext ). [I would encourage readers to look at this article directly. it is quite powerful]:

        -- 79% women, 24% were 30-39 years old/31% were 40-49yo/25% were 50-59yo, 85% white, 41% urban/42% suburban, 41% from the US/35% UK, 57% nonhospitalized and not seen an urgent care/35% urgent care or ED/8% hospitalized

        -- >91% took more than 35 weeks to recover (they did not look longer...)

        -- participants had 56 symptoms across an average of 9 organ systems

        -- these symptoms were often moderate or severe, were multiple, and lasted for at least 35 weeks

        -- In terms of symptom prevalence (only commenting on those >60%): fatigue in 98%, post exertional malaise 90%, shortness of breath 78%, palpitations 68%, tightness of chest 75%, muscle aches 69%, dry cough 66%

            -- and, fatigue and post-exertional malaise persisted for at least 28 weeks without changing (post exertional malaise was initially found in 35%, increased to about 70% by 8 weeks, and persisted at that level for at least 28 weeks), brain fog and memory issues persisted in about 60% (brain fog/memory issues were in the 40% range for the first six weeks, then increased to 60%), headaches and insomnia continued in about 45%, and sensorimotor symptoms persisted in about 60%.

        -- the three most debilitating symptoms were fatigue (2652 of 3762 respondents), breathing issues (2242 of 3762), and cognitive dysfunction (1274 of 3762)

        -- 85.9% (84.8%-87.0%) of participants had relapses primarily triggered by exercise, physical or mental activity, and stress

            -- 52.8% characterized their relapses as occurring in an irregular pattern and 52.4% in response to a specific trigger (physical activity in 71%, stress in 59%, exercise in 54%, and mental activity in 46%); also, 34.3% of menstruating women experienced relapses during menstruation, and 35.2% just before menstruation

            -- also, 164 (4.4%) participants had a temporary break in symptoms, to return later

         -- 1700 (45.2%) required a reduced work schedule as compared to pre-illness, and 839 (22.3%) were not working at the time of the survey because of the illness

         -- cognitive dysfunction or memory issues were common in all age groups (88%)

-- another study of 45 women (29 who had had mild-to-moderate Covid infection about three months earlier, and 16 controls) had a 6-minute walk test (6MWT) and pulmonary function tests. Mean age 56, BMI 26. (see https://physoc.onlinelibrary.wiley.com/doi/epdf/10.1113/EP089965 ):

    -- 17 of the 29 participants were symptomatic: cough, shortness of breath, fatigue, loss of taste/smell, joint/muscle aches, dermatitis/hair loss

    -- no difference between those Covid-infected and controls in resting and 6MWT heart rate, blood pressure, oxygen saturation, carboxyhemoglobin saturation, or perceived dyspnea

    -- but, the change in heart rate from rest to post-6MWT was different between those who had Covid versus controls (difference of 52 versus 65 bpm)

    -- and, by stratifying the Covid group from symptomatic versus asymptomatic, those symptomatic with shortness of breath had:

        -- % predicted 6MWT: 79% versus 101% in both asymptomatic Covid and controls [this lowered % predicted 6MWT tracked with decreased DLCO on PFTs]

        -- change in heart rate while walking: increase of 32 bpm, versus 56 in asymptomatic Covid and 65 in controls

        -- change in heart rate one minute after: decrease of 13 bpm versus 23 in asymptomatic Covid and 29 in controls

    -- for the other symptoms in the PASC patients, there were also statistically significant differences or nearly so in those having joint/muscle aches, fatigue, loss of taste/smell, and cognitive impairment

    -- PFTs showed that there was a statistically significant difference in those having had Covid for total lung capacity, vital capacity, functional residual capacity, and residual volume

    -- so, this study did show marked differences in the chronotropic response and recovery from a 6MWT, notably in those who had symptoms consistent with PASC, as well as some significant differences in PFTs

-- a very small study comparing 10 PASC patients (9 of whom had mild Covid infections) but who had unexplained exercise intolerance, with 10 controls who never had Covid (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354807/pdf/main.pdf ):

    -- no one who had had covid infection had abnormal chest CTs, anemia, or problems with lung or heart function by invasive cardiopulmonary exercise testing done 11 months after their Covid infection

        -- but they did have markedly reduced peak exercise oxygen consumption (70% versus 31% of predicted), impaired systemic oxygen extraction (arterial-mixed venous oxygen content difference/arterial oxygen content ratio: 0.49 versus 0.78), though there was a preserved peak cardiac index

    -- so, bottom line from the study, there were no evident long-term cardiopulmonary disease sequelae from the Covid infection, but instead pretty dramatic peripheral limits to aerobic exercise as assessed by oxygen consumption and mixed venous oxygen saturation

    -- another small study done at the same institution (Brigham and Women's Hospital) found that in 9 patients with PASC evaluated almost a year after a mild Covid infection were compared to controls that included patients with postural tachycardia syndrome (POTS): autonomic dysfunction, pain, brain fog, fatigue, and dyspnea surveys were abnormal in the PASC and POTS groups: see https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26286

        -- tilt table testing reproduced the majority of PASC symptoms, with similar orthostatic reductions (20 mmHg) in those with PASC and POTS, though with POTS they were associated with hyperventilation. Dysautonomia was frequent in both syndromes but milder in those with PASC. Also small fiber neuropathy on biopsy was found in 89% with PASC versus 60% with POTS, suggesting that low-grade inflammation of small vessels played a role with PASC

        -- of course, both PASC and POTS are both the well-defined long-term effects of Covid infection. It would not be surprising if there were significant overlap or combinations of the symptoms...

-- it may be notable that similar findings in terms of fatigue, memory/cognitive issues, muscle/joint pain have been found in patients with chronic fatigue syndrome, and the same Brigham Hospital group found some similar findings to post-covid on extensive examination, including small fiber neuropathy and postural orthostatic tachycardia, likely related to peripheral vascular dysregulation (see https://journal.chestnet.org/action/showPdf?pii=S0012-3692%2821%2900256-7 ). These chronic fatigue patients have also been found to have worsening symptoms with exercise, and probably it is not useful for us/patients to push exercise too much. A graded exercise therapy program did find some functional improvement (though was associated with higher numbers of reported adverse events and more patients withdrawing from this exercise approach versus counseling therapies or controls). see https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/chronic-fatigue_research.pdf

Commentary:

-- as with other studies in long Covid/PASC, the above reinforced that it happens very frequently in people with mild to moderate disease (the majority in the large study above not seeking any care at the time of infection), younger people ( >50% of them were 30-50yo), and may have delayed onset. Of note in the study the issue of post exertional malaise and brain fog/memory issues were reported much more frequently 6 to 8 weeks after the infection

-- it was also notable above that in the large epidemiologic surveys, there were specific triggers for symptoms (specifically exercise, physical or mental activity, and stress) and that some people had a break in symptoms with subsequent recurrence

-- though the physiologic studies were quite small and 3 of them were done by the same group of investigators, it was interesting that the finding of post-exercise malaise was related to peripheral autonomic/small nerve fiber dysfunction and not to specific cardiopulmonary abnormalities; also prior suggestions that long Covid was similar to myalgic encephalomyelitis/chronic fatigue syndrome were largely borne out by these physiologic studies

   -- the study on PFTs, though small, did suggest some intrinsic pulmonary differences: there are bound to be variations in the physiological parameters measured. it is clear that some people do have persisting documentable pulmonary findings and some have persistent severe/disabling pulmonary disease. these small studies suggest that at least for some people, there might be predominantly peripheral autonomic nervous system abnormalities. would have been interesting to have the small sample of PASC patients in the above invasive cardiopulmonary exercise testing to have had PFTs as well, to compare with the other PFT study

--one issue of concern to me is that the actual data in the literature about the prevalence of long Covid suggests that probably on the order of tens to hundreds of millions of people (about one in seven of infected, or more in some studies) in the United States have it. My experience in an inner-city health center in Boston is that we don’t see it so much. I’m not sure what the discordance is, perhaps we are not asking enough and patients with milder symptoms do not necessarily bring them up. Not sure. But this is also my finding for chronic fatigue syndrome....

 

Limitations:

-- these large-scale survey data reflect a biased sample: self-reported data through the Internet selects for younger, more highly educated, computer/smart-phone savvy people. The numbers above in the large surveys may therefore not be generalizable to the larger population

-- the physiologic studies noted above, in contrast, were quite small, limiting their potential utility for understanding the general population

-- all of these studies predated omicron. and there are likely differences in PASC manifestations, incidence, and perhaps physiology (eg, omicron seems to have less tropism for the lungs). we will need to wait several more months to see how the longer-term PASC symptoms evolve with omicron

so, again, impressive (actually, depressive) numbers of people do develop long covid/PASC. and, as with other studies, typically more in younger people and in those with mild to moderate covid infections.  This all is really concerning, given that this younger group tends to be more dismissive to getting covid, since there is pretty wide-spread feeling that covid is a mild disease, so why get vaccinated?? And, it certainly does seem that covid is likely to become another endemic viral infection. But, unlike rhinoviruses or influenza, or even the 4 seasonal coronaviruses, there is still very large concern about long covid, its longterm effects (?lifetime in some) on patients' symptoms, functionality, and overall quality of life.

geoff

 

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