covid: long covid 1 year after mild disease

 A couple of articles were just published on the prevalence of long covid in patients with mild covid infections:

 

1. retrospective nationwide Israeli study assessed long covid one year after mild initial infections (see covid long covid after mild infection BMJ2023 in dropbox, or https://www.bmj.com/content/bmj/380/bmj-2022-072529.full.pdf

 

Details:

-- 1,913,234 patients had a PCR test done for SARS-CoV-2 between March 2020 and October 2021

    -- 299,870 were PCR positive and included in the study; the same number were chosen who were PCR negative (with matching of the major potential confounders, and propensity matching for the weaker confounders)

    -- 70,862 were vaccinated and 229,008 were not

    -- 72,317 had wild-type SARS-CoV-2; 97,963 had alpha variant; and 58,728 had delta variant

        -- though the delta variant was not included in the full analysis, since there was insufficient follow-up time

-- median age 25, 51% female, 76% unvaccinated

-- prediabetes 14%, diabetes 4%, hypertension 8%, obesity 21%, smoking 10%, and all others <5% (ie, pretty healthy group)

-- socioeconomic level: low 32%, medium 35%, high 33%

-- 70 health conditions were assessed over time (these were the conditions reported in the literature as being associate with long covid)

 

-- main outcomes: risk of long covid outcomes in unvaccinated people infected with SARS-CoV-2 vs uninfected people, adjusted for age, sex, SARS-CoV-2 variant; and, risk in vaccinated patients with breakthrough SARS-CoV-2 infection compared with unvaccinated infected controls

    -- long covid outcomes were stratified by early (30-180 days) vs late (180-360 days) in the main analysis

 

Results:

-- unvaccinated participants, major health outcomes:

    --anosmia and dysgeusia:

        -- early (30-180 days): HR 4.59 (3.63-5.8), with risk difference per 10,000 patients between those with positive vs negative PCRs of 19.6 (16.9-22.4)

        -- late (180-360 days): HR 2.96 (2.29-3.82), with risk difference 11.0 (8.5-13.6)

    -- concentration and memory impairment:

        -- early (30-180 days): HR 1.85 (1.56-2.17), with risk difference 12.8 (9.6-16.1)

        -- late (180-360 days): HR 1.69  (1.45-1.96), with risk difference 13.3 (9.4-17.3)

    -- dyspnea:

        -- early (30-180 days): HR 1.79 (1.68-1.90), with risk difference 85.7 (76.9-94.5)

        -- late (180-360 days): HR 1.30 (1.22-1.38), with risk difference 35.4 (26.3-44.6)

    -- weakness:

        -- early (30-180 days): HR 1.78 (1.69-1.88), with risk difference 108.5 (98.4-118.6)

        -- late (180-360 days): HR 1.30 (1.22-1.37), with risk difference 50.2 (39.4-61.1)

    -- palpitations

        -- early (30-180 days): HR 1.49 (1.35-1.64), with risk difference 22.1 (16.8-27.4)

        -- late (180-360 days): HR 1.16  (1.05-1.27), with risk difference 8.3 (2.4-17.3)

    -- streptococcal tonsillitis:

        -- early (30-180 days): HR 1.18 (1.09-1.28), with risk difference 13.4 (6.8-19.9)

        -- late (180-360 days): HR 1.12  (1.05-1.20), with risk difference 16.6 (7.4-25.9)

    -- dizziness:

        -- early (30-180 days): HR 1.14 (1.06-1.23), with risk difference 11.4 (4.7-18.1)

        -- late (180-360 days): HR 1.17 (1.09-1.26), with risk difference 16.7 (8.6-24.8)

    -- overall, the yearly burden measured was highest for weakness (risk difference 136.0), dyspnea (107.4) and streptococcal tonsillitis (31.8)

--  in a more detailed analysis:

    -- review of the monthly data (not a primary outcome) found that the hazard ratios for dyspnea, palpitations, weakness, cough, and chest pain peaked close to the infection and declined after the second month, though the HRs for dyspnea and weakness still remained high into the late phase (vs palpitations and chest pain, which reverted to baseline within 8 months)

    -- anosmia and dysgeusia peaked 6 months after covid diagnosis, with a slow subsequent decline

    -- concentration and memory impairment were consistently elevated throughout, peaking at 4 months (also found for hair loss)

    -- streptococcal pharyngitis remained elevated from 4 to 8 months post covid

-- A further analysis found that, though those with positive PCRs did have an increased risk for pulmonary disease, they did not have more prescriptions for drugs than those who were PCR negative, suggesting no increased risk of more severe pulmonary conditions

 
-- analysis by age groups: 

    -- 0-4yo: conjunctivitis and dyspnea, elevated only during the early phase

    -- 5-11yo: increased streptococcal tonsillitis in both phases, conjunctivitis in the early phase, and sore throat in the late phase

    -- 12-18yo: increased streptococcal tonsillitis during both early and late phases, and anosmia/dysgeusia, dyspnea, and weakness during the early phase

    -- 19- 40 yo: high risk for and anosmia and dysgeusia, dyspnea, concentration and memory impairment, and weakness in both early and late time periods

    -- 41-60 yo: highest number of long Covid health outcomes that were elevated in both the early and late time periods, especially anosmia and dysgeusia, dyspnea, weakness, and concentration and memory impairment

    -- >60yo: increased risk of hair loss, weakness, dyspnea, and chest pain in the early phase, though dyspnea remained elevated throughout the late phase

 

-- Unvaccinated male versus female: overall comparable hazard ratios, though women in the early period had significantly higher risk of hair loss, and the risk of weakness and dyspnea were reported more often in women than men

 

-- By virus variants:
    -- similar clinical manifestations of long Covid in those infected with the wild-type and alpha variants

    -- combining those two groups and comparing them to the delta variant for symptoms 30 to 90 days after infection: no significant difference in outcomes

 

-- By vaccination status:

    -- the vaccine became available during this study: 14,090 people older than 12 years old were vaccinated (median age 35)

    -- breakthrough infections at least 14 days after the second dose of vaccine found:

        -- significantly lower risk of prolonged dyspnea in those vaccinated versus unvaccinated, HR 1.58 (1.18-2.12)

        -- and excluding patients were vaccinated more than three months before (with perhaps waning immunity): no difference

 

Commentary:

-- as we know only too well, covid has been devastating, with 600 million confirmed cases worldwide in the past 2 years, >6.5 million deaths as of Nov 2022

-- this study was able to assess several SARS-CoV-2 variants over time, including the wild-type, alpha, and delta ones

-- the presence of long covid has been well-documented in patients, from those asymptomatic to very severely affected by the initial infection (though the definition of long covid is still not consistent, with some using 4 weeks as the measure and others longer)

-- some documented risk factors for long covid include older age, pre-existing comorbidities (obesity, cardiovascular disease, chronic lung disease, chronic kidney disease,  hypertension and diabetes), and female sex

-- and, several studies have documented quite high numbers of patients who have long covid:

    -- a UK study found that 1.5 million people have reported it (2.4% of the population!!!)

-- and several studies have found long covid even after asymptomatic infections: eg see http://gmodestmedblogs.blogspot.com/2021/08/covid-long-covid-update-including-in.html

 

-- this study, with its plethora of data (and Israel has the robust system of country-wide datasets and frequent Covid testing, and much of the data was from electronic health records and not self-reports through questionnaires), confirmed the relatively high level of post-covid symptoms after mild covid infection, and confirmed that some of these symptoms remained for the 8-12 month period; several of them (eg concentration and memory loss, anosmia and dysgeusia) actually peaked 4-6 months post-infection

    -- the long Covid occurred in all age groups. it was most common in those 41-60yo, and there were somewhat different manifestations of long Covid depending on the age group

    -- there were only small differences between men and women in long Covid

    -- no apparent difference between the wild type and alpha variant, as well as in a briefer analysis with the delta variant (despite the fact that these variants seem to have different patterns of transmission, virulence, and disease severity)

    -- vaccination in those over 12 years old (the vaccination criterion at that time) seemed to confer significant protection and developing long Covid

        -- other studies have found this as well: http://gmodestmedblogs.blogspot.com/2022/07/covid-long-covid-decreased-with.html

    -- overall most of the long Covid symptoms in this study were relatively mild, and largely affected the lungs

    -- and, atypically, this study actually looked at absolute differences between those infected versus not infected with SARS-CoV-2, and not just the relative differences

        -- these absolute differences in long covid translate into a small percentage of those infected. But small percentages in huge numbers of infected people lead to large numbers with long covid...

-- contrary to expectations, perhaps, was that the highest number of long Covid symptoms persisting at least six months after Covid infection were reported in the 41 to 60-year-old age group, where the risk of 5 of the outcomes remained significantly higher throughout the year after infection

-- the findings of increased streptococcal pharyngitis and conjunctivitis in kids in particular may reflect altered immunity from the Covid infection, leading to increased bacterial and viral infection susceptibility

    -- and, if there is any immunologic mechanism to increased infections from other respiratory pathogens, this may become a more prominent issue as we have become less aggressive in social distancing and masking at this time

Limitations:

-- given the 1-year followup, only the wild-type and alpha variants were checked (the more recent ones did not have sufficient followup time). Their preliminary analysis did show that delta did not seem to be any worse, but this analysis was limited to only 90 days post Covid, and several of the sequelae became more prominent after that time. And, of course, there are no long-term data on the omicron or subsequent omicron variants

    -- preliminary studies have suggested that the omicron variant is less likely associated with long covid: http://gmodestmedblogs.blogspot.com/2022/10/covid-long-covid-less-common-with.html (this blog refers to several prior ones, including one on the 2-year followup in China, which found much higher rates of long covid than in this study. But we should remember that by the time of omicron, many people in the West had had at least some vaccination and also at least one covid infection, which might significantly alter their immunity and the potential for long covid. in this light, there is the ongoing experiment on this: China is a country with very few past covid infections and not great vaccination rates (and with likely a less potent vaccine); so the current situation should reveal lots about the real intensity of new infections (if we get real data on that....)

-- those with Covid did have more blood tests and potentially more pickups of some of the post Covid findings, such as nonalcoholic fatty liver disease

-- this study was based on the use of the Pfizer vaccine, the predominant one in Israel, and may not extend to other vaccines

    -- also, because this study was based in one country (though there was a large representation of that population in that country), generalization to other areas may be fraught

So, this was an intricate observational study with lots and lots of data confirming the quite high prevalence of post Covid symptoms after a mild infection, and that several of the symptoms extended for up to one year:
    -- 13 of the long Covid outcomes were  most prominent

    -- of note, these symptoms occurred in all age groups, though the specific symptoms did vary by age 

    -- these differences were apparent in all the Covid variants assessed 

    -- vaccination did seem to help prevent long Covid symptoms 

 ---------------------------------------------------------------------------------------------------------------------------------------------------------------

2. and, another (see covid long covid after mild infection JAMA2021, or doi:10.1001/jama.2021.5612):

 

Details:

-- 393 covid seropositive Swedish hospital workers and 1072 seronegative controls were followed  

    --median age 43, 83% women; chronic illness in 22% seropositive patients vs 24% seronegative (no more detailed information included)

    -- only patients with mild disease were included in the seropositive group, and only patients who were persistently seronegative with blood tests every 4 months were included in the seronegative group

    -- symptoms were assessed at the 8-month followup visit (January 2021), reporting via smartphone app the presence of any of 23 predefined symptoms (stratified by <2 months, > 2 months, >4 months, and >8 months) as well as the severity (mild, moderate, or severe)

        -- those with at least 1 symptom for at least 2 months had assessment for functional impairment (via the Sheehan Disability Scale, assessed as 1-3 being mild, 4-6 moderate and 7-10 severe)

 

 

Results:

 -- common moderate-to-severe longterm symptoms, comparing seropositive to seronegative (control) participants, listing only those with at least 4% prevalence (their table has the rest, including sleeping disorder, headache, palpitations, concentration impairment, muscle/joint pain, memory impairment):

    -- any symptom:

        -- >2 months: 26% vs 9%

        -- >4 months: 21% vs 7%

        -- >8 months: 15% vs 3%

    -- anosmia:

        -- >2 months: 15% vs 0.6%

        -- >4 months: 11% vs 0.4%

        -- >8 months: 9% vs 0.1%

    -- fatigue:

        -- >2 months: 8% vs 5%

        -- >4 months: 7% vs 4%

        -- >8 months: 4% vs 1.5%

    -- ageusia:

        -- >2 months: 8% vs 0.6%

        -- >4 months: 5% vs 0.3%

        -- >8 months: 4% vs 0.1%

    -- dyspnea:

        -- >2 months: 4% vs 1%

        -- >4 months: 3% vs 0.9%

        -- >8 months: 2% vs 0.3%

 

-- Functional impairment:

 

-- comparing seropositive vs seronegative participants:

    --8% of seropositive (vs 4% seronegative) had moderately to markedly disrupted work life, RR 1.8 (1.2-2.9)

    --15% ( vs 6%) had symptoms that moderately or markedly disrupted their social life, RR 2.5 (1.8-3.6)

    --12% (vs 5%) reported moderately to markedly disrupted home life, RR 2.3 (11.6-3.4)

 

Commentary:

-- as in other studies, the main symptoms for long covid, which largely tracked for at least 8 months, were anosmia, fatigue, ageusia and dyspnea (see

-- this was a brief report without much granular detail, but there were pretty remarkable numbers of people (1 in 7) with mild Covid infections who had moderately to markedly functional impairment

 

Limitations:

-- this study was based on participant's subjective assessment of their symptoms and the level of their intensity/functional sequelae affecting their work, homelife and social life. And their could be recall bias as well as different participant's interpretation of the symptom intensity

    -- though the actually reported functional disability should reflect those participants' actual effects of these symptoms on their individual lives

-- as a short report, there was not a lot of granular data to help interpret who the participants were (eg, what were the comorbidities?, and how severe were they?)

 

so, this study reinforces that though covid has morphed into a more benign disease than initially, there are a lot of people who seem to have long-term sequelae of even mild infections.

-- and this is an important message to the population at large that even getting a mild infection can really impact their lives for a long time (the 2-year studies confirm this)

-- the real concern here is that covid infections have become normalized (just another "cold") by much of the population. and despite increases in covid at this time, there are not a lot of mitigation strategies being used (masks, avoiding large events, minimizing exposures in outside venues (restaurants, theaters, etc))

geoff

-----------------------------------

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

  

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

1. 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 and is the easiest to view blogs and displays more at a time.

2. go to http://gmodestmedblogs.blogspot.com/ to see the blogs in reverse chronological order

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

  -- 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

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