covid: long-term sequelae in large VA study

 A new huge VA study found a large array of persistent symptoms in veterans after nonhospitalized Covid-19 infection (see covid long covid VA study nature2021 in dropbox, or doi.org/10.1038/s41586-021-03553-9 ) 

 

Details: 

    -- 73,435 people in the VA system who survived at least 30 days after Covid-19 diagnosis and were not hospitalized were compared to 4,990,835 nonhospitalized veterans who did not have covid, from 1March 2020 to 31December 2020 

-- covariates assessed included age, race, sex, receipt of long-term care, number of patient encounters, number of hospitalizations, number of outpatient prescriptions, and number of outpatient eGFR measurements in the year before enrollment. They also included the Area Deprivation Index at the residency address of the patients as a surrogate measure for socio-economic issues 

--median followup 126 days 

 

Results: 

-- non-hospitalized controls had no increase in symptoms: HR 1.03 (0.94-1.12) for all HRs and 1.03 (0.95-1.12) for neoplasms and accidental injuries 

-- covid patients after 30 days of illness, vs all VA users, at 6 months: 

    -- excess deaths: 8.39 (7.09-9.58) per 1,000 patients 

    -- outpatient care:  20% increase, HR 1.20 (1.19-1.21), excess burden 33.22/1,000 patients 

    -- in evaluating 379 diagnoses, 380 classes of medication and 62 laboratory tests after the first 30 days (all with hazard ratios >1 and p<6.57x10^-5, with excess burden per 1000 patients with Covid-19 at 6months): 

        -- respiratory conditions: excess burden 28.51 (26.40) per 1000 patients

            -- respiratory failures, insufficiency, arrest: 4.67 (3.96-5.28) 

            -- use of bronchodilators: 22.23 (20.68-23.67) 

            -- anti-asthmatic agents: 8.87 (7.65-9.97) 

            -- steroids: 7.65 (5.67-9.50) 

        -- CNS: 

            -- overall signs and symptoms: 14.32 (12.16-16.36) 

            -- neurocognitive disorders: 3.17 (2.24-3.98) 

            -- headache: 4.10 (2.49-5.58) 

        -- mental health: 

            -- sleep-wake disorders: 14.53 (11.53-17.36) 

            -- trauma and stress-related disorders: 8.93 (6.62-11.09) 

            -- use of analgesics: 

               -- nonopioids: 19.97 (17.41-22.40) 

               -- opioids: 9.39 (7.21-11.43) 

            -- antidepressants:7.83 (5.19-10.30) 

            --  benzos/sedatives/anxiolytics: 22.23 (20.68-23.67) 

    -- metabolic disorders: 

            -- lipid disorders: 12.32 (8.18-16.24) 

            -- diabetes: 8.23 (6.63-9.95) 

            -- obesity: 9.53 (7.55-11.37) 

            -- anti-lipid meds: 11.56 (8.73-14.19) 

            -- oral hypoglycemic: 5.39 (3.99-6.64) 

            -- insulin: 4.95 (3.87-5.90) 

            -- and, increased LDL, triglycerides and A1c 

    -- general well-being: 

        -- malaise/fatigue: 12.64 (11.24-13.93) 

        -- musculoskeletal pain: 13.89 (9.89-17.71) 

        -- anemia: 4.79 (3.53-5.93) 

        -- and, decreased hematocrit, decreased hemoglobin, and decreased serum albumin 

    -- cardiovascular: 

        -- hypertension: 15.18 (11.53-18.62) 

        -- cardiac dysrhythmias: 8.41 (7.18-9.53) 

        -- chest pain 10.08 (8.63-11.42) 

       -- coronary atherosclerosis: 4.38 (2.96-5.67) 

       -- heart failure 3.94 (2.97-4.80) 

       -- and, increased use of beta blockers, calcium channel blockers, loop diuretics, thiazides, antiarrhythmics 

    -- gastrointestinal: 

        -- esophageal disorders: 6.90 (4.58-9.07) 

        -- gastrointestinal disorders: 3.58 (2.15-4.88) 

        -- dysphagia: 2.3 (1.79-3.76) 

        -- abdominal pain: 5.73 (3.7-7.62) 

        -- and, increased use of laxatives, antiemetics, histamine antagonists, antidiarrheal agents, as well as increased levels of ALT 

-- the adjusted hazard ratios were up to 5.84 for “autoinflammatory syndromes”, 3.9 for respiratory failure, 3.05 for pulmonary embolism, 2.8 for pneumothorax, and most were in the 1.3 to 1.9 range 

 

-- Comparing 13,654 people hospitalized with Covid-19 versus 13,997 hospitalized with influenza who survived at least 30 days after hospital admission (patients hospitalized with influenza between 1October2016 and 29February2020): 

    -- those with Covid had 51% increased risk of death, HR 1.51 (1.30-1.76), with excess of 28.79 (19.52-36.85) per 1000 persons at six months, as well as increased risk of requiring outpatient care 

    -- those with Covid had higher burden of pulmonary, neurologic, mental health, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, coagulation disorders, and pulmonary emboli versus those with influenza 

 

Commentary: 

-- there was a remarkably high incidence of long-term sequelae to Covid, six months after infection, involving many different organ systems/clinical manifestations 

-- there was a gradient of risk of Covid sequelae in those with mild infection, increasing in those with severe cases of Covid 

-- this increased risk of Covid sequelae in hospitalized patients dwarfed that of those hospitalized with influenza infection 

-- the results of the study supplement those of several other studies, including: 

    -- http://gmodestmedblogs.blogspot.com/2021/06/covid-really-scary-brain-changes-in.html , which documented significant neuroimaging changes related to the infection 

    -- http://gmodestmedblogs.blogspot.com/2021/06/covid-large-long-covid-study.html , another large retrospective US cohort study finding long-term sequelae in 14% of those <65yo 

    -- http://gmodestmedblogs.blogspot.com/2021/04/covid-long-covid-predictors.html another study finding about a 14% increased risk of symptoms more than 28 days after infection, most reported for the first time 3 to 4 weeks after symptom onset 

-- it is unclear what the cause of this increased risk of sequelae is: ? Direct viral invasion, ? Aberrant immune response/hyperactivation/autoimmunity, associated large social changes (from lockdown, social isolation, decreased employment, diet/exercise changes, and the known association with increased psychiatric issues/substance use: see http://gmodestmedblogs.blogspot.com/2021/04/covid-long-term-psych-and-neuro-effects.html ) 

 

Limitations: 

-- as a retrospective study, it is not possible to definitively attribute causality, given that there might well have been unmeasured confounding variables 

-- as a VA study, this was primarily a male population of veterans, and not necessarily generalizable to the overall population 

-- there might also be a difference in those veterans who are hospitalized in the VA system (as above) versus in non-VA hospitals, further limiting generalizability 

-- there was not much associated granular data, including psychosocial or socioeconomic conditions, or other potentially important social variables (diet, exercise, support systems, etc.), or even the age distribution of those having Covid 

-- some of the increase in diagnosis and meds may reflect selection bias: those with baseline diagnoses of respiratory issues, for example, may be more likely to get covid infections, though in this study they mostly assessed those who had non-severe/non-hospitalized infections 

-- how many different individuals had these sequelae? Was it a few individuals who had multiple sequelae, versus a broad group of individuals? 

-- comparisons between Covid and influenza in hospitalized patients might have been fraught since these were at different time periods, and the angst of Covid likely outweighed that of influenza at the time

-- we do not know how many of these long Covid symptoms will persist, since our experience with SARS-CoV-2 is limited to the last year and a half 

-- we also do not know whether those developing mild symptoms postvaccination have the same long-term problems. There are some suggestive studies suggesting that long-term sequelae might be better after vaccination (a small recent study of patients hospitalized with Covid-19 actually had some improvement in symptoms: https://www.medrxiv.org/content/10.1101/2021.03.11.21253225v3 ) 

-- and we have no information on those with asymptomatic infections developing the above types of sequelae 

 

So, 

-- these post-covid sequelae occurred in non-hospitalized (ie not severe) cases of Covid-19 in this really huge VA study, corresponding to 2,070,615 person-years of follow-up 

-- in those with severe cases, these sequelae far exceeded those hospitalized with influenza as well as with negative controls, likely pointing to SARS-CoV-2 virus-specific sequelae 

-- this large database complements a large number of prior studies on long Covid, highlighting the potentially severe long-term consequences of even mild infections, and providing even more compelling information on the need for vaccination 

    -- and, patients do need to know that even mild infections can be associated with a significant increase in long-term and potentially debilitating symptoms... 

geoff

 

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