COVID raises risk of long-term brain injury, large U.S. study finds

Authors: Julie Steenhuysen September 22, 2022 Yahoo News

People who had COVID-19 are at higher risk for a host of brain injuries a year later compared with people who were never infected by the coronavirus, a finding that could affect millions of Americans, U.S. researchers reported on Thursday.

The year-long study, published in Nature Medicine, assessed brain health across 44 different disorders using medical records without patient identifiers from millions of U.S. veterans.

Brain and other neurological disorders occurred in 7% more of those who had been infected with COVID compared with a similar group of veterans who had never been infected. That translates into roughly 6.6 million Americans who had brain impairments linked with their COVID infections, the team said.

“The results show the devastating long-term effects of COVID-19,” senior author Dr. Ziyad Al-Aly of Washington University School of Medicine said in a statement.

Al-Aly and colleagues at Washington University School of Medicine and the Veterans Affairs St. Louis Health Care System studied medical records from 154,000 U.S. veterans who had tested positive for COVID from March 1, 2020 to Jan. 15, 2021.

They compared these with records from 5.6 million patients who did not have COVID during the same time frame, and another group of 5.8 million people from the period just before the coronavirus arrived in the United States.

Al-Aly said prior studies looked at a narrower group of disorders, and were focused largely on hospitalized patients, whereas his study included both hospitalized and non-hospitalized patients.

Memory impairments, commonly referred to as brain fog, were the most common symptom. Compared with the control groups, people infected with COVID had a 77% higher risk of developing memory problems.

People infected with the virus also were 50% more likely to have an ischemic stroke, which is caused by blood clots, compared with the never infected group.

Those who had COVID were 80% more likely to have seizures, 43% more likely to have mental health issues, such as anxiety or depression, 35% more likely to have headaches and 42% more likely to suffer movement disorders, such as tremors, compared with the control groups.

Researchers said governments and health systems must devise plans for a post-COVID world.

“Given the colossal scale of the pandemic, meeting these challenges requires urgent and coordinated – but, so far, absent – global, national and regional response strategies,”

High cholesterol, overweight and reduced physical stamina are long COVID sequelae in young adults

Authors: University of Zurich Summary: 6, 2022:Science Daily

As the Covid-19 pandemic evolves, the issue of post-infection consequences is growing in significance. Does Long Covid impact previously healthy young adults? Although this group is of great societal importance, representing the next generation and the backbone of the workforce, the intermediate-term and long-term effects of SARS-CoV-2 infections have scarcely been researched in this population. Available original research tends to focus on sufferers who were hospitalized, the elderly or those with multiple morbidities, or restricts evaluations to a single organ system.

Long Covid implications in young Swiss military personnel

A new study, funded by the Swiss Armed Forces, and conducted under the leadership of Patricia Schlagenhauf, Professor at the Epidemiology, Biostatistics and Prevention Institute of the University of Zurich (UZH), has now evaluated possible Long Covid implications in young Swiss military personnel. The study, published in the journal Lancet Infectious Diseases, was done between May and November 2021 with 29 female and 464 male participants with a median age of 21. 177 participants had confirmed Covid-19 more than 180 days prior to the testing day, and the control group was made up of 251 SARS-CoV-2 serologically negative individuals. Unlike other studies the novel test battery also evaluated cardiovascular, pulmonary, neurological, ophthalmological, male fertility, psychological and general systems.

Despite overall recovery also sequelae after recent infections remain

The findings show that young, previously healthy, non-hospitalized individuals largely recover from mild infection and that the impact of the SARS-CoV-2 virus on several systems of the body is less than that seen in older, multi-morbid or hospitalized patients. However, the study also provided evidence that recent infections — even mild ones — can lead to symptoms such as fatigue, reduced sense of smell and psychological problems for up to 180 days, as well as having a short-term negative impact on male fertility. For non-recent infections — more than 180 days back — these effects were no longer significant.

Specific constellation carries risk of developing metabolic disorders

For those with non-recent infections, however, the study — which had a long follow-up — provided evidence of a potentially risky constellation: “Increased BMI, high cholesterol and lower physical stamina is suggestive of a higher risk of developing metabolic disorders and possible cardiovascular complications,” says principal investigator Patricia Schlagenhauf. “These results have societal and public-health effects and can be used to guide strategies for broad interdisciplinary evaluation of Covid-19 sequelae, their management, curative treatments, and provision of support in young adult populations.”

Significant landmark study points the way

The study, conducted in collaboration with clinics at the University Hospital Zurich and Spiez Laboratory, is novel in that it quantitatively evaluated multi-organ function using a sensitive, minimally invasive test battery in a homogenous group of people several months after a Covid-19 infection. A valuable facet of the study was the control group, serologically confirmed to have had no SARS-CoV-2 exposure. “This combination of a unique test battery, a homogenous cohort and a control group make this a very powerful, landmark study in the evidence base on Long Covid in young adults,” says Schlagenhauf.

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Journal Reference:

  1. Jeremy Werner Deuel, Elisa Lauria, Thibault Lovey, Sandrine Zweifel, Mara Isabella Meier, Roland Züst, Nejla Gültekin, Andreas Stettbacher, Patricia Schlagenhauf. Persistence, prevalence, and polymorphism of sequelae after COVID-19 in unvaccinated, young adults of the Swiss Armed Forces: a longitudinal, cohort study (LoCoMo)The Lancet Infectious Diseases, 2022; DOI: 10.1016/S1473-3099(22)00449-2

COVID-19 vaccine may not stop long term effects on older adults

Authors: Associated Press

New U.S. research on long COVID-19 provides fresh evidence that it can happen even after breakthrough infections in vaccinated people, and that older adults face higher risks for the long-term effects.

In a study of veterans published Wednesday, about one-third who had breakthrough infections showed signs of long COVID.

A separate report from the Centers for Disease Control and Prevention found that up to a year after an initial coronavirus infection, 1 in 4 adults aged 65 and older had at least one potential long COVID health problem, compared with 1 in 5 younger adults.

Long COVID refers to any of more than two dozens symptoms that linger, recur or first appear at least one month after a coronavirus infection. These can affect all parts of the body and may include fatigue, shortness of breath, brain fog and blood clots.

Coronavirus vaccines that help prevent initial infections and serious illnesses provide some protection against long COVID but mounting research shows not as much as scientists had first hoped.

The veterans study published in Nature Medicine reviewed medical records of mostly white male veterans, aged 60, on average. Of the 13 million veterans, almost 3 million had been vaccinated last year, through October.

About 1%, or nearly 34,000, developed breakthrough infections. Lead author Dr. Ziyad Al-Aly noted that the study was done before the highly contagious omicron variant appeared at the end of the year and said the rate of breakthrough infections has likely increased.

Breakthrough infections and long COVID symptoms were more common among those who had received Johnson & Johnson’s single-dose shot compared with two doses of either Moderna or Pfizer vaccines. Whether any had received booster shots is not known; the first booster wasn’t OK’d in the U.S. until late September.

Overall, 32% had long COVID symptoms up to six months after breakthrough infections. That’s compared with 36% of unvaccinated veterans who had been infected and developed long COVID.

Vaccination reduced the chances for any long COVID symptoms by a “modest” 15%,” although it cut the risk in half for lingering respiratory or clotting problems, said Al-Aly, a researcher with Washington University and the Veterans Affairs health system in St. Louis. These symptoms included persistent shortness of breath or cough and blood clots in lungs or veins in the legs.

Patients who have taken Johnson & Johnson’s COVID-19 vaccine have tested positive for virus more often than their Moderna and Pfizer counterparts.FREDERIC J. BROWN/AFP via Getty Images

Infectious disease expert Dr. Kristin Englund, who runs a center for long COVID patients at the Cleveland Clinic, said the Nature Medicine study mirrors what she sees at her clinic. Long COVID patients there include people who were vaccinated and received boosters.

“As we have no clear treatments for long COVID, it is important for everyone to get vaccinated and use other proven methods of prevention such as masking and social distancing in order to prevent infections with COVID and thus long COVID,” Englund said.

The CDC report, released Tuesday, used medical records for almost 2 million U.S. adults from the start of the pandemic in March 2020 to last November. They included 353,000 who had COVID-19. Patients were tracked for up to a year to determine if they developed any of 26 health conditions that have been attributed to long COVID.

Those who had COVID were much more likely than other adults without COVID to develop at least one of these conditions, and risks were greatest for those aged 65 and older. Information on vaccination, sex and race was not included.

Breathing problems and muscle aches were among the most common conditions.

Older adults’ risks were higher for certain conditions, including strokes, brain fog, kidney failure and mental health problems. The findings are worrisome because those conditions can hasten older adults’ needs for long-term care, the report authors said.

They stressed that routine assessment of all COVID patients “is critical to reduce the incidence” of long COVID.

Long COVID: which symptoms can be attributed to SARS-CoV-2 infection?

Authors: Christopher E Brightling Rachael A Evans Published:August 06, 2022DOI:https://doi.org/10.1016/S0140-6736(22)01385-X The Lancet

Mortality rates following SARS-CoV-2 infection have decreased as a consequence of public health policies, vaccination, and acute antiviral and anti-inflammatory therapies.1 However, in the wake of the pandemic, post-acute sequelae of COVID-19, or long COVID, has emerged: a chronic illness in people who have ongoing multidimensional symptomatology and disability weeks to years after the initial infection.2 Early reports of long COVID prevalence, summarized in a systematic review examining the frequency and variety of persistent symptoms after COVID-19, found that the median proportion of people who had at least one persistent symptom 60 days or more after diagnosis or at least 30 days after recovery from COVID-19 infection was 73%. 3 However, the estimated prevalence depends on the duration, population, and symptoms used to define long COVID. More recently, community-based studies have suggested a lower prevalence of persistent symptoms; 4 whereas among people who were hospitalised following COVID-19 infection, a high proportion do not fully recover (50–70%).56

The number of COVID-19 cases continues to rise and now exceeds 500 million worldwide.1 Consequently, the number of people with long COVID is similarly increasing. Indeed, the UK Office for National Statistics (ONS) survey up to May, 2022 estimated that 2 million people in the UK had self-reported long COVID. 8 Of these people, 72% reported having long COVID for at least 12 weeks, 42% for at least 1 year, and 19% for at least 2 years. Consistent with other studies, fatigue was the most common symptom in the ONS survey, followed by breathlessness, cough, and muscle ache.45678 Risk factors for long COVID are female sex, obesity, middle age (35–65 years), living in areas of greater socioeconomic deprivation, and the presence of another activity-limiting health condition.156 Importantly, health-care use is increased in those with long COVID, with increased general practitioner consultation rates.

How many of the symptoms currently attributed to long COVID actually represent pre-existent disease or are unrelated to COVID-19 is uncertain. Symptoms that were present before SARS-CoV-2 infection are often not recorded or assessed by recall. In The Lancet, Aranka V Ballering and colleagues 10  report the findings of a longitudinal cohort study conducted in the north of the Netherlands between April, 2020, and August, 2021, where 23 somatic symptoms were assessed using 24 repeated measurements in digital COVID-19 questionnaires. The study was embedded within the large, population-based Lifelines COVID-19 cohort. The main strengths of this study were that participants were their own control, with the pattern and severity of symptoms assessed before and 3–5 months after SARS-CoV-2 infection, and were also compared with a matched control group of COVID-19-negative participants. Of the 76 422 participants, 4231 (5·5%) had COVID-19 and were compared with 8462 matched controls. Participants had a mean age of 53·7 years (SD 12·9), 46 329 (60·8%) were female, and nearly all were of White ethnicity. The proportion of participants who had at least one core symptom of substantially increased severity to at least moderate was 21·4% (381 of 1782) in COVID-19-positive participants versus 8·7% (361 of 4130) in COVID-19-negative controls. Thus, this study found that core symptoms were attributed to COVID-19 in 12·7% of participants, or approximately one in eight. This is a major advance on previous long COVID prevalence estimates, as it includes a matched control group without SARS-CoV-2 infection and accounts for symptoms that were present before infection.

The pattern of symptomatology observed by Ballering and colleagues 0  was similar to previous reports, with fatigue and breathlessness among the most common symptoms, but other symptoms such as chest pain were more common in people who had COVID-19 than in COVID-19-negative controls. Ballering and colleagues10  propose a core symptom set to be considered as part of the case definition for long COVID. Although an agreed diagnostic core symptom set would inform clinical pathways and research, the study by Ballering and colleagues 10 did not fully consider the impact on mental health, it was conducted in one region in the Netherlands, and it did not include an ethnically diverse population; thus the concept of a core symptom set will require further validation. Importantly, the study by Ballering and colleagues 10  does not provide new mechanistic insights, which are key to uncovering new therapeutic targets. In other studies, clustering of patient-reported outcomes has identified different severity groups of long COVID and identified increased systemic inflammation in people with very severe long COVID.5, 6

 How patient-centred outcomes, together with biomarkers, can further refine long COVID diagnosis and inform precision medicine approaches warrants further consideration. Encouragingly, emerging data from other studies suggest that the proportion of newly infected people developing long COVID is reduced in people who have received vaccination before SARS-CoV-2 infection,11  and might be lower in people infected with the omicron variant than those infected with earlier variants.2

 Findings from the ONS survey suggested that vaccination following infection might reduce the symptom burden of long COVID after the first dose, with sustained improvement after a second dose13  Whether acute treatments for COVID-19 affect the likelihood of developing long COVID or its severity is unknown.

Current evidence supports the view that long COVID is common and can persist for at least 2 years after SARS-CoV-2 infection, although severe debilitating disease is present in a minority. The long COVID case definition needs to be further improved, potentially to describe different types of long COVID, of which better mechanistic understanding is crucial. This will lead to personalised multimodality treatments that can be implemented to manage the increasingly high number of people with long COVID.

CEB has received consultancy and or grants paid to his institution from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Genentech, Roche, Sanofi, Regeneron, Mologic, and 4DPharma for asthma and chronic obstructive pulmonary disease research. RAE has received consultancy fees from AstraZeneca on the topic of long COVID and from GlaxoSmithKline on digital health, and speaker’s fees from Boehringer Ingelheim on long COVID. RAE holds a National Institute for Health and Care Research (NIHR) clinician scientist award CS-2016-16-020.

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    Coronavirus Resource Centre.https://coronavirus.jhu.edu/Date: 2022Date accessed: June 27, 2022View in Article 
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    Assessment of the frequency and variety of 511 persistent symptoms among patients with COVID-19: a systematic review.JAMA Netw Open. 2021; 4e2111417View in Article 
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    Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study.Lancet Respir Med. 2021; 9: 1275-1287View in Article 
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    Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study.Lancet Respir Med. 2022; (published online April 23.)https://doi.org/10.1016/S2213-2600(22)00127-8View in Article 
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    Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study.Lancet Respir Med. 2022; (published online May 11.)https://doi.org/10.1016/S2213-2600(22)00126-6View in Article 
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    • Office for National Statistics
    Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK.https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowing coronaviruscovid19infectionintheuk/1june2022Date: June 1, 2022Date accessed: June 27, 2022View in Article 
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9

Long COVID after breakthrough SARS-CoV-2 infection

Authors: Ziyad Al-AlyBenjamin Bowe & Yan Xie 

Nature Medicine volume 28, pages1461–1467 (2022)

Abstract

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

Main

The post-acute sequelae of SARS-CoV-2 infection—also referred to as Long COVID—have been characterized1. Increasingly, vaccinated individuals are being diagnosed with COVID-19 as a result of breakthrough SARS-CoV-2 infection (BTI)2,3. Whether people with BTI experience post-acute sequelae is not clear. Addressing this knowledge gap is important to guide public health policy and post-acute COVID-19 care strategies.

Here we leverage the breadth and depth of the electronic healthcare databases of the US Department of Veterans Affairs to address the question of whether people with BTI develop post-acute sequelae. We characterize the risks and 6-month burdens of a panel of prespecified outcomes in a cohort of people who experienced BTI after completion of vaccination in the overall cohort and by care setting of the acute phase of the disease (that is, whether people were not hospitalized, hospitalized or admitted to an intensive care unit (ICU) during the first 30 days after a positive test). We then undertake a comparative evaluation of the magnitude of risk in people with BTI versus those with SARS-CoV-2 infection and no prior vaccination and, separately, hospitalized people with BTI versus those hospitalized with seasonal influenza.

Results

Post-acute sequelae in BTI versus controls without SARS-CoV-2 infection

There were 33,940 and 4,983,491 participants in the BTI group and a contemporary control group of users of the Veterans Health Administration from 1 January 2021 to 31 October 2021 with no record of a positive SARS-CoV-2 test, respectively. BTI participants had a positive SARS-CoV-2 test with prior record of a complete vaccination defined following Centers for Disease Control and Prevention (CDC) guidelines at 14 days after first Janssen (Johnson & Johnson)(Ad26.COV2.S) vaccination and 14 days after second Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) vaccination. The demographic and health characteristics of the BTI and the control groups before and after weighting are presented in Supplementary Tables 14. During the enrollment period, the overall rate of BTI within those fully vaccinated was 10.60 (95% CI: 10.52, 10.70) per 1,000 persons at 6 months; rates of breakthrough by vaccine type are presented in Supplementary Data Table 1.

For all analyses, we provide two measures of risk: (1) we estimated the adjusted HRs of a set of incident prespecified outcomes in people with BTI versus the control group; and (2) we estimated the adjusted excess burden of each outcome due to BTI per 1,000 persons 6 months after a positive SARS-CoV-2 test on the basis of the difference between the estimated incidence rate in individuals with BTI and the control group. Assessment of standardized mean differences of participant characteristics (from data domains including diagnoses, medications and laboratory test results) after application of weighting showed that they are well-balanced in each analysis of incident outcomes (Supplementary Fig. 1).

Compared to the contemporary control group, people who survived the first 30 days of BTI exhibited an increased risk of death (HR = 1.75, 95% CI: 1.59, 1.93) and excess burden of death estimated at 13.36 (95% CI: 11.36, 15.55) per 1,000 persons with BTI at 6 months; all burden estimates represent excess burden and are given per 1,000 persons with BTI at 6 months (Fig. 1). People with BTI also had an increased risk of having at least one post-acute sequela of SARS-CoV-2 (PASC) (HR = 1.50, 95% CI: 1.46, 1.54; burden of 122.22, 95% CI: 115.31, 129.24) (Supplementary Table 5).

figure 1
Fig. 1: Risk and 6-month excess burden of post-acute sequelae in people with BTI compared to the contemporary control group.

Compared to the control group, 30-day survivors of BTI exhibited increased risk of post-acute sequelae in the pulmonary (HR = 2.48 (2.33, 2.64); burden of 39.82 (36.83, 42.99)) and several extrapulmonary organ systems, including cardiovascular disorders (HR = 1.74 (1.66, 1.83); burden of 43.94 (39.72, 48.35)), coagulation and hematologic disorders (HR = 2.43 (2.18, 2.71); burden of 13.66 (11.95, 15.56)), fatigue (HR = 2.00 (1.82, 2.21); burden of 15.47 (13.21, 17.96)), gastrointestinal disorders (HR = 1.63 (1.54, 1.72); burden of 37.68 (33.76, 41.80)), kidney disorders (HR = 1.62 (1.47, 1.77); burden of 16.12 (13.72, 18.74)), mental health disorders (HR = 1.46 (1.39, 1.53); burden of 45.85 (40.97, 50.92)), metabolic disorders (HR = 1.46 (1.37, 1.56); burden of 30.70 (26.65, 35.00)), musculoskeletal disorders (HR = 1.53 (1.42, 1.64); burden of 19.81 (16.56, 23.31)) and neurologic disorders (HR = 1.69 (1.52, 1.88); burden of 11.60 (9.43, 14.01)). Risk and excess burden of each individual sequela and by organ system are provided in Extended Data Fig. 1 (Supplementary Table 6) and Fig. 1 (Supplementary Table 5), respectively.

The results were consistent in analyses considering a historical control group (n = 5,785,273) as the referent category (Extended Data Fig. 2 and Supplementary Table 7) and, separately, people who were vaccinated for SARS-CoV-2 and did not experience a BTI (n = 2,566,369) as another alternative control group (Extended Data Fig. 3 and Supplementary Table 8).

The risk of death was increased in the 30–90 days and also increased, but to a lesser extent, in the 90–180 days after a positive SARS-CoV-2 test (Supplementary Table 9). The risk of incident sequelae was increased in the 30–90 days after a positive SARS-CoV-2 test. In the period between 90 days and 180 days after testing positive, there was increased risk of both incident sequalae—albeit in lesser magnitude than the risk in days 30–90—and increased risk of recurrent or persistent sequalae (Supplementary Table 9).

Compared to the contemporary control group, there was increased risk of death, at least one PASC and organ involvement in people who were not immunocompromised before BTI (Extended Data Fig. 4a and Supplementary Table 10); the risks were generally higher in those who were immunocompromised before BTI (Extended Data Fig. 4a and Supplementary Table 10). Analyses of people with BTI showed that the risks of death, at least one PASC and organ system involvement were consistently higher in people who were immunocompromised versus those who were not before BTI (Extended Data Fig. 4b and Supplementary Table 10).

Of people with BTI, analyses by vaccine type suggested that there is no statistically significant difference in risk of post-acute death among the three SARS-CoV-2 vaccines (Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273) and Janssen (Johnson & Johnson) (Ad26.COV2.S)). Both BNT162b2 and mRNA-1273 were associated with decreased risk of at least one PASC: pulmonary and extrapulmonary organ involvement. There was no statistically significant difference in risk of any of these outcomes between BNT162b2 and mRNA-1273 (Supplementary Table 11).

Post-acute sequelae in BTI by care setting of the acute phase of the disease

The demographic and health characteristics of people with BTI who were not hospitalized, who were hospitalized and who were admitted to ICU during the acute phase of the disease before and after weighting are provided in Supplementary Tables 12 and 13. Evaluation of standardized mean differences of baseline participant characteristics after the application of the weighting suggested good balance (Supplementary Fig. 2).

Compared to the control group of people without evidence of SARS-CoV-2 infection, people who were not hospitalized during the first 30 days of BTI exhibited an increased risk of death (HR = 1.29 (1.12, 1.49); burden of 7.77 (5.62, 10.24)); the risk was further increased in those who were hospitalized (HR = 2.69 (2.33, 3.12); burden of 24.79 (20.39, 29.86)) and was highest in those who were admitted to ICU (HR = 5.68 (4.55, 7.09); burden of 60.02 (46.85, 76.19)). The risk of having at least one post-acute sequela was evident in non-hospitalized people (HR = 1.25 (1.20, 1.30); burden of 77.60 (68.40, 87.04)), was further increased in those who were hospitalized (HR = 2.95 (2.80, 3.10); burden of 334.10 (315.90, 352.53)) and was highest in those admitted to ICU (HR = 3.75 (3.38, 4.16); burden of 421.39 (383.37, 459.56)) (Fig. 2 and Supplementary Table 14).

figure 2
Fig. 2: Risk and 6-month excess burden of post-acute sequelae in those with BTI by acute phase care setting.

People who were not hospitalized exhibited small but significant increased risk of post-acute sequelae, including cardiovascular, coagulation and hematologic, gastrointestinal, mental health, metabolic, musculoskeletal and pulmonary disoders, as well as increased risk of fatigue (Fig. 2 and Supplementary Table 14). The risks were further increased in people who were hospitalized (Fig. 2 and Supplementary Table 14) and highest in those admitted to the ICU (Fig. 2 and Supplementary Table 14). Analyses of individual sequela are presented in Extended Data Fig. 5 and Supplementary Table 15.

Post-acute sequelae in BTI versus SARS-CoV-2 infection without prior vaccination

To place the magnitude of risk of post-acute sequelae in people with BTI in broad context of post-acute COVID-19 manifestations, we developed a comparative approach to evaluate the risk of organ system involvement in people with BTI (n = 33,940) versus people with SARS-CoV-2 infection and no prior history of vaccination (n = 113,474) (Supplementary Tables 1 and 16). Assessment of standardized mean differences of baseline characteristics in the weighted cohorts suggested good balance (Supplementary Figs. 3 and 4 and Supplementary Tables 4 and 17).

People with BTI exhibited lower risk of death (HR = 0.66 (0.58, 0.74); burden of −10.99 (−13.45, −8.22); negative values denote reduced burden in BTI relative to SARS-CoV-2 infection) and lower risk of post-acute sequelae (HR = 0.85 (0.82, 0.89); burden of −43.38 (−53.22, −33.31)) compared to those with SARS-CoV-2 infection and no prior history of vaccination (Fig. 3 and Supplementary Table 18). Comparatively, the risk of post-acute sequelae in all the examined organ systems was lower in people with BTI versus those with SARS-CoV-2 infection without prior vaccination. BTI was associated with lower risk of 24 of the 47 sequelae examined compared to those with SARS-CoV-2 infection without prior vaccination (Extended Data Fig. 6 and Supplementary Table 19). The reduced risk was evident (albeit weak) in those who were immunocompromised and in those who were not immunocompromised (Supplementary Table 20).

figure 3
Fig. 3: Risk and 6-month excess burden of post-acute sequelae in people with BTI compared to those with SARS-CoV-2 infection without prior vaccination.

Analyses within each care setting suggested that the risk reduction in BTI versus SARS-CoV-2 infection on both the relative (HR) and absolute (burden) scale generally becomes increasingly more pronounced as the acuity of the care setting increased (from non-hospitalized to admitted to ICU) (Fig. 4 and Supplementary Table 21). BTI was associated with less risk of death and at least one PASC in all care settings. There was also a consistently reduced risk of hematologic and coagulation disorders and pulmonary disorders in BTI versus SARS-CoV-2 infection without prior vaccination across all care settings.

figure 4
Fig. 4: Risk and 6-month excess burden of post-acute sequelae in those with BTI compared to those with SARS-CoV-2 infection without prior vaccination by acute phase care setting.

Post-acute sequelae in people hospitalized with BTI versus seasonal influenza

We developed a comparative analysis to better understand how people hospitalized with BTI (n = 3,667) fare relative to those who are hospitalized with seasonal influenza (n = 14,337). Demographic and health characteristics before and after weighting are provided in Supplementary Tables 22 and 23. Examination of standardized mean differences of baseline characteristics after application of overlap weighting demonstrated good balance (Supplementary Fig. 5).

Compared to people who were hospitalized with seasonal influenza, people with BTI who were hospitalized during the acute phase of the disease and survived the first 30 days exhibited an increased risk of death (HR = 2.43 (2.02, 2.93); burden of 43.58 (31.21, 58.26)) and increased risk of having at least one post-acute sequela (HR = 1.27 (1.19, 1.36); burden of 87.59 (63.83, 111.40)) (Extended Data Fig. 7 and Supplementary Table 24). People with BTI exhibited increased risk of sequelae in all the examined organ systems compared to those with seasonal influenza. Results of individual sequalae are presented in Supplementary Fig. 6 and Supplementary Table 25.

Positive and negative outcome controls

To assess whether our approach reproduces established knowledge, we tested the association between SARS-CoV-2 infection without prior vaccination and the risk of fatigue (a cardinal post-acute sequela of COVID-19, where, based on prior evidence, we would expect a positive association). The results showed that, compared to the contemporary control group, people with SARS-CoV-2 infection and without prior vaccination exhibited increased risk of fatigue (HR = 2.79 (2.57, 303)) (Extended Data Table 1a).

To assess the putative presence of spurious associations, we tested the association between BTI and several negative outcome controls where there was no biologic plausibility or epidemiologic evidence that an association is expected. We used the same data sources, cohort building process, covariate selection approach (including predefined and algorithmically selected high-dimensional covariates), weighting method and interpretation of results. The results suggested no significant association between BTI and risk of any of the negative outcome controls (Extended Data Table 1a).

To further test the rigor of our approach, we tested as a pair of negative exposure controls receipt of influenza vaccination in odd-numbered (n = 605,453) versus even-numbered (n = 571,291) calendar days between 1 March 2020 and 15 January 2021. Examination of the associations of receipt of influenza vaccine on odd-numbered versus even-numbered calendar days and each outcome yielded non-significant results, consistent with our a priori expectations for a successful application of negative exposure controls (Extended Data Table 1b).

Discussion

In this study of 33,940 people with BTI, 4,983,491 in the contemporary control, 5,785,273 in the historical control, 2,566,369 in the vaccinated control, 113,474 in the SARS-CoV-2 infection without prior vaccination group and 14,337 in the seasonal influenza group, we show that, compared to non-infected controls, people who survive the first 30 days of BTI exhibited increased risk of death and post-acute sequelae in the pulmonary and several extrapulmonary organ systems. The risks of death and post-acute sequelae were evident among non-hospitalized people, further increased among hospitalized people and highest among people who were admitted to ICU during the acute phase of the disease. Our comparative approach shows that risks of death and post-acute sequelae were lower in people with BTI versus people with SARS-CoV-2 infection without prior vaccination. Analyses of BTI versus SARS-CoV-2 infection without prior vaccination within the same care setting showed that this risk reduction was progressively more evident as care acuity of the acute phase of the disease increased from non-hospitalized to hospitalized and admitted to ICU and was consistently most pronounced for coagulation and pulmonary disorders. In comparative analyses among people who were hospitalized during the acute phase of the disease, those with BTI exhibited higher risks of death and post-acute sequelae than those with seasonal influenza. The constellation of findings shows that the burden of death and disease experienced by people with BTI is not trivial. Our comparative analyses provide a framework to better evaluate and contextually understand risks of the post-viral condition in people with BTI versus non-infected controls, versus SARS-CoV-2 infection without prior vaccination and versus seasonal influenza. The findings show that vaccination only partially reduces the risk of death and post-acute sequelae, suggesting that reliance on it as a sole mitigation strategy may not most optimally reduce the risk of the long-term health consequences of SARS-CoV-2 infection. Our results emphasize the need for continued optimization of primary prevention strategies of BTIs and will inform post-acute care approaches for people with BTI.

We examined the risk of death and post-acute sequelae in those with BTI versus several controls of people without evidence of SARS-CoV-2 infection, including (1) a contemporary control of people exposed to the same broader forces of the pandemic (lockdowns and economic, social and environmental stressors); (2) a historical control from a pre-pandemic era that represents a baseline unaffected by the disruptions of the pandemic; and (3) a vaccinated control group. The results show two key findings: (1) Long COVID, including increased risks of death and myriad post-acute sequelae in the pulmonary and extrapulmonary organ systems, also manifests in vaccinated individuals who experience a BTI; and (2) the range of post-acute sequelae in various organ systems in BTI does not appear to be different than COVID-19 without prior vaccination1,4,5,6,7,8,9,10,11,12. Our analyses of BTI versus SARS-CoV-2 infection without prior vaccination show that, comparatively, the magnitude of the risks of death and post-acute sequelae was lower in people with BTI versus those with SARS-CoV-2 infection who had not been previously vaccinated for it. These results show that, although vaccination may partially reduce the risks of post-acute death and disease, to most optimally reduce this burden requires continued emphasis on primary prevention of breakthrough SARS-CoV-2 infection as a goal of public health policy.

Although the absolute rates are smaller than in those with SARS-CoV-2 infection without prior vaccination, given the scale of the pandemic and the potential for breakthrough cases to continue to accumulate, the overall burden of death and disease after BTI will likely be substantial, will further add to the toll of this pandemic and will represent an additional strain on already overwhelmed health systems. In planning and development of health resources, governments and health systems should take into account the care needs of people with post-acute sequelae after BTI13.

Our analyses suggest that this risk reduction (of post-acute sequelae) was most pronounced in recipients of BNT162b2 and mRNA-1273 vaccines (compared to Ad26.COV2.S). Although these results recapitulate evidence of vaccine effectiveness in the acute phase of COVID-19, the mechanism or mechanisms underlying this carry-through effect of risk reduction from the acute to the post-acute phase of the disease is not entirely clear. One putative interpretation of these results is that vaccine-induced reduction in severity of the acute infection may then translate into less long-term risk of post-acute health outcomes. In other analyses, we also show that the reduced risk of post-acute sequelae in people with BTIs was partially eroded in people with immunocompromised status, suggesting a putative immune-related mechanism in the expression of post-acute sequelae that may be influenced by vaccination.

We also show that the risk of post-acute sequelae is higher in people with BTI than in people with seasonal influenza—a well-characterized respiratory viral illness. This extends previous evidence showing that the risk of post-acute sequelae in people with SARS-CoV-2 infection was higher than those with seasonal influenza and again emphasizes the importance of prevention of both SARS-CoV-2 infection and BTI1.

This study has several strengths. To our knowledge, it is the first large study to characterize the risks of post-acute sequelae of BTI at 6 months. We leveraged the vast national healthcare databases of the US Department of Veterans Affairs (the largest nationally integrated healthcare delivery system in the United States) to characterize the risk and 6-month burden of a comprehensive set of prespecified incident health outcomes in patients who survived the first 30 days of BTI versus several control groups (contemporary, historical and vaccinated controls). In addition to evaluating risk of BTI versus those with no evidence of SARS-CoV-2 infection in the overall cohort and by care setting of the acute phase of the disease (non-hospitalized, hospitalized and admitted to ICU), we also undertook a comparative evaluation of BTI versus SARS-CoV-2 infection in people who had not been previously vaccinated and, separately, BTI versus seasonal influenza. We used advanced statistical methodologies and adjusted through weighting for a battery of predefined covariates selected based on prior knowledge and algorithmically selected covariates from high-dimensional data domains, including diagnoses, prescription records and laboratory test results. We evaluated the rigor of our approach by testing positive and negative outcome controls to determine whether our approach would produce results consistent with pre-test expectations.

The study also has several limitations. The BTI and SARS-CoV-2 infection groups included only those who had a positive test for SARS-CoV-2 and did not include those who may have had an infection with SARS-CoV-2 but were not tested; however, if present, this will bias the estimates toward the null. Although the Veterans Affairs population is comprised of mostly men, it includes 8–10% women, which, across the groups in our study, included 1,300,744 female participants. Although we adjusted through the overlap weighting approach for a large battery of predefined and algorithmically selected covariates, and although our approach demonstrated good balance for more than 734 covariates (including all those that were available in the data but not included in the weighting process) from several data domains, including diagnoses, prescription medications and laboratory test results, and resulted in successful testing of positive outcome controls and negative outcome controls, we cannot completely rule out residual confounding. Our approach does not evaluate the severity of each outcome. Finally, the COVID-19 global pandemic is highly dynamic. As vaccine uptake continues to increase, as vaccine schedules continue to be optimized, as vaccine effectiveness wanes over time since vaccination, as booster vaccinations are deployed, as treatment strategies of the acute phase of COVID-19 continue to improve and as new variants of the virus emerge, it is likely that the epidemiology of BTI and its downstream sequelae may also change over time.

In sum, our findings provide evidence of increased risk of death and post-acute sequelae in people with BTI compared to controls with no evidence of SARS-CoV-2 infection; the risks were reduced in comparative analyses involving BTI versus SARS-CoV-2 infection without prior vaccination. Our results show that SARS-CoV-2 vaccination before infection only partially reduced the risk of death and post-acute sequelae. Measures for the prevention of breakthrough infections are needed to most optimally reduce the risk of the long-term health consequences of SARS-CoV-2 infection.

Methods

All participants who were eligible for this study were enrolled; no a priori sample size analyses were conducted to guide enrollment. All analyses were observational, and investigators were aware of participant exposure and outcome status. A summary of the major design elements is presented in Supplementary Table 26, and an analytic flowchart is provided in Supplementary Fig. 7.

Setting

Cohort participants were identified from the US Veterans Health Administration (VHA) electronic health databases. The VHA provides healthcare to discharged veterans of the US armed forces in a nationally integrated network of healthcare systems that includes more than 1,415 healthcare facilities. Veterans enrolled in the VHA have access to a comprehensive medical benefits package that includes outpatient services; preventive, primary and specialty care; mental health care; geriatric care; inpatient hospital care; extended long-term care; prescriptions; home healthcare; medical equipment; and prosthetics. The VHA healthcare databases are updated daily.

Cohorts

We first identified users of the VHA who were alive on 1 January 2021 (n = 5,430,912). Use of the VHA was defined as having record of use of outpatient or inpatient service, receipt of medication or use of laboratory service with the VHA healthcare system in the 2 years prior (Supplementary Fig. 8). Among these, 163,024 participants had a record of a first positive SARS-CoV-2 test from 1 January 2021 to 31 October 2021, and 5,140,387 had no record of any positive SARS-CoV-2 test between 1 January 2020 and 1 December 2021. Participants were followed until 1 December 2021.

To construct a group of people with BTI, we selected, from those with a positive SARS-CoV-2 test (n = 163,024), those with a record of completion of an Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination before the date of their first positive SARS-CoV-2 test (n = 34,863). Completion of vaccination was defined following CDC guidelines at the 14th day after the second shot of the mRNA-1273 or BNT162b2 vaccination series or the 14th day after the first shot of the Ad26.COV2.S vaccination. Setting the date of first positive SARS-CoV-2 test as time zero (T0), we then selected those alive 30 days after T0, resulting in a cohort of 33,940 participants in the BTI group.

We then constructed several control groups; the rationale for each of these control groups is provided in Supplementary Fig. 9. To build a contemporary control group of people with no evidence of SARS-CoV-2 infection, we then used the 5,140,387 users of the VHA who had no record of a SARS-CoV-2-positive test. Among these participants, we randomly assigned a T0 to each participant in the group on the basis of the distribution of the T0 dates in those with BTI. We finally selected those who were alive 30 days after their T0 (n = 4,983,491). The contemporary control group represents contemporaneous users of the VHA who were subject to the broader forces of the pandemic but did not contract SARS-CoV-2 infection. Of these, the 2,566,369 who had record of a SARS-CoV-2 vaccination before their T0 served as a vaccinated control group. The vaccinated control group represents contemporaneous users of the VHA who share the characteristic of being vaccinated with the breakthrough group and have a major distinction in that they did not contract SARS-CoV-2 infection subsequent to their vaccination.

To build an alternate control group during a period of time where participants were not subject to the influence of the pandemic, we identified users of the VHA who were alive on 1 January 2018 (n = 6,084,973) and who had no history of a positive SARS-CoV-2 test (n = 5,938,519). After randomly assigning a T0 in 2018 on the basis of the distribution of the calendar dates of T0 in those with BTI, 5,785,273 were alive 30 days after T0. Participants were followed until 1 December 2018. This group served as the historical control group.

To build the group of people with SARS-CoV-2 infection and without prior vaccination as a means of investigating the effect of prior vaccination on the risk of post-acute sequalae, we identified, from the 163,024 people with a first positive SARS-CoV-2 test from 1 January 2021 to 31 October 2021, 118,185 who had no record of any SARS-CoV-2 vaccination up through 30 days after first positive SARS-CoV-2 test (T0). We then selected the 113,474 who were alive 30 days after T0 to comprise the group of people with SARS-CoV-2 infection and no prior vaccination.

Finally, to compare post-acute sequelae of those hospitalized with BTI during the acute phase of the illness to those hospitalized with seasonal influenza, we separately identified 15,160 VHA users hospitalized with positive seasonal influenza test 5 days before or 30 days after the test between 1 October 2016 and 29 February 2020. We set the date of the positive seasonal influenza test as T0. To ensure no overlap with the BTI group, participants who had no record of a positive SARS-CoV-2 test were then selected (n = 14,431). From these, we selected 14,337 who were alive 30 days after their T0 to constitute the seasonal influenza group. Duration of follow-up was randomly assigned on the basis of follow-up in the BTI group.

Data sources

Data used in this study were obtained from the VHA Corporate Data Warehouse (CDW). Within CDW, the patient data domain provided information on demographic characteristics; the outpatient encounters domain and inpatient encounters domain provided information on health characteristics, including data on timing and location of interactions with the healthcare system, diagnoses and procedures; the pharmacy and barcode medication administration domains provided medication records; and the laboratory results domain provided laboratory test information in both outpatient and inpatient settings5,6. The COVID-19 Shared Data Resource provided information on SARS-CoV-2 test results and SARS-CoV-2 vaccination status. The 2019 Area Deprivation Index (ADI) at each cohort participant residential address was used as a contextual measure of socioeconomic disadvantage14.

Post-acute sequelae

We prespecified a set of outcomes based on prior evidence on the post-acute sequelae of SARS-CoV-2 infection—also referred to as Long COVID4,5,6,7,8,9,10,11,12. Outcomes were defined using validated definitions leveraging information from several data domains, including diagnoses, prescription medications and laboratory test results, at the time of first record of occurrence in the data5,6,15,16,17,18,19,20,21. Incident post-acute sequelae were examined in a cohort with no record of the health condition in the 2 years before T0. We additionally examined outcomes of death and having at least one of post-acute sequelae that was defined at the time of the first incident prespecified post-acute sequelae in each participant.

Additionally, we defined a set of outcomes where we aggregated the prespecified post-acute sequelae, where applicable, by organ system. These included cardiovascular disorders, coagulation and hematologic disorders, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, metabolic disorders, musculoskeletal disorders, neurologic disorders and pulmonary disorders. All outcomes were assessed starting from 30 days after T0.

Covariates

We included a set of predefined covariates based on prior knowledge4,5,6,7,8,9,10,11,12,19,22,23,24,25,26 and algorithmically selected covariates. Predefined covariates included demographic information (age, race and sex); contextual information (ADI); measures of the intensity of healthcare interaction in the 2 years before T0, including the number of outpatient visits, the number of inpatient visits, the number of unique medications the participant received a prescription for and the number of routine blood panels that were performed; and prior history of receiving an influenza vaccination. We also included smoking status as a covariate. Health characteristics included prior history of anxiety, cancer, cardiovascular disease, cerebrovascular disease, chronic kidney disease, peripheral artery disease, dementia, depression, type 2 diabetes mellitus and chronic obstructive pulmonary disease, and measures of estimated glomerular filtration rate, systolic and diastolic blood pressure, and body mass index (BMI). We also included, as measures of spatiotemporal differences, the calendar week of enrollment and geographic region of receipt of care defined by Veterans Integrated Services Networks (VISN).

In consideration of the dynamicity of the pandemic, for analyses that compared BTI, SARS-CoV-2 infection without prior vaccination and the contemporary control, additional covariates included SARS-CoV-2 testing capacity, SARS-CoV-2 positivity rates, hospital system capacity (the total number of inpatient hospital beds) and inpatient bed occupancy rates (the percentage of hospital beds that were occupied) as well as a measure of the proportions of SARS-CoV-2 variants by Health and Human Services region26. These measures were ascertained for each participant in the week before cohort enrollment at the location of the healthcare system at which they received care. In analyses of the vaccinated control, we additionally included calendar week of first vaccination shot. All continuous covariates were treated as natural cubic splines unless heavily skewed toward zero.

In addition to the predefined covariates, we leveraged the high dimensionality of VA data where we developed and deployed a high-dimensional variable selection algorithm to identify covariates that may potentially confound the examined associations27. Using classifications from the Clinical Classifications Software Refined version 2021.1, available from the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality, more than 70,000 ICD-10 diagnoses codes in the year before T0 for each participant were classified into 540 diagnostic categories28,29,30. Using the VA drug classification system, 3,425 different medications were classified into 543 medication classes31,32. Finally, laboratory results from 38 different laboratory measurements were classified into 62 laboratory test abnormalities, defined by being above or below the corresponding reference ranges, on the basis of the recorded Logical Observation Identifiers Names and Codes. Of the high-dimensional variables that occurred at least 100 times in participants in each group (up to 821), we selected the top 100 variables with the highest relative risk for differences in group membership for inclusion in models.

Statistical analysis

Mean (standard deviation) and frequency (percentage) of select characteristics are reported in the BTI group, SARS-CoV-2-infected group without prior vaccination, the contemporary control group, the historical control group, the vaccinated control group and the seasonal influenza group, where appropriate. Characteristics of those with BTI by hospitalization status are additionally presented. Vaccination characteristics for those with BTI are reported as well as BTI rates per 1,000 persons at 6 months for those vaccinated from 1 January to 31 October 2021.

To balance baseline characteristics, including predefined and high-dimensional variables across comparison groups, we applied an overlap weighting approach in our analyses. In brief, logistic regressions were constructed for probability of group membership of the groups being compared, using the predefined and high-dimensional covariates as independent variables, in separate subcohorts with no prior history of the outcome being examined, estimating propensity scores of the probability of group assignment33,34. In consideration of variability in duration of potential follow-up, calendar week of enrollment was included to balance length of follow-up between cohorts (uncensored duration of follow-up was included for comparison versus seasonal influenza). Propensity scores were then used in construction of the overlap weights whose application achieved similar baseline characteristic distributions across groups while providing higher weights to those with baseline characteristics more similar to those in other groups. Weights were then applied to Cox survival models to estimate HRs, where follow-up started 30 days after the date of testing positive. Standard errors were estimated by applying the robust sandwich variance estimator method. Covariate balance among all predefined and high-dimensional variables were assessed for each model through the standardized mean difference, where a difference <0.1 was taken as evidence of balance. We estimated the incidence rate difference (referred to as excess burden) between groups per 1,000 participants at 6 months after the start of follow-up based on the difference in survival probability in the relevant groups.

We first examined the risk and excess burden of individual post-acute sequelae, post-acute sequelae by organ system, at least one post-acute sequela and death between the BTI group, those with SARS-CoV-2 infection without prior vaccination and the contemporary control. We then compared risks of the BTI group with the historical control and, separately, with the vaccinated control.

Further analyses were conducted to better understand the risk in BTI versus the contemporary control. To investigate risk of post-acute sequalae before and after 90 days of follow-up, we conducted analyses that examined risk during the first 30–90 days, and during the 90–180 days, after T0. Examination of the risk from the 90–180 days was done overall, for incident outcomes during this period (where there was no record of the outcome during the 30–90-day period) and for recurrent or persistent outcomes during this period (where there was a prior record of the outcome during the 30–90-day period). We then comparatively evaluated the risks between the BTI and contemporary control based on their immunocompromised status, where immunocompromised status was defined (according to the CDC definition) by a history of organ transplantation, advanced kidney disease (an estimated glomerular filtration rate of less than 15 ml/min/1.73 m2 or end-stage renal disease), cancer, HIV or conditions with prescriptions of more than 30-day use of corticosteroids or immunosuppressants, including systemic lupus erythematosus and rheumatoid arthritis. We lastly compared the risks and burden of death, at least one PASC, pulmonary disorders and extrapulmonary disorders within those with BTI by type of vaccination received.

We then examined the risk and excess burden associated with BTI by care setting of the acute phase of the disease. Risks were estimated for individual sequelae and risks and excess burden of organ system involvement, at least one post-acute sequela and death in those with a BTI who were not hospitalized, who were hospitalized and who were admitted to ICU during the 5 days before and 30 days after their positive SARS-CoV-2 test compared to the contemporary control group.

We additionally examined differences in risk and burden between BTI and SARS-CoV-2 infection without prior vaccination by severity of the acute phase of the disease (non-hospitalized, hospitalized and admitted to ICU).

Finally, we compared the risks and excess burden of individual post-acute sequelae, post-acute sequelae by organ system, at least one post-acute sequela and death between those hospitalized with BTI and those hospitalized with seasonal influenza.

Positive and negative controls

We examined, as positive outcome controls, the risks of fatigue in those with SARS-CoV-2 infection without prior vaccination compared to the contemporary and historical control groups as a means of testing whether our approach would reproduce established knowledge8,9,10,11,12.

The application of negative outcome control may help detect both suspected and unsuspected sources of spurious biases. We, therefore, tested comparing BTI to the contemporary and historical controls, the risk of atopic dermatitis, accidental poisoning, accidental injury, fitting of a hearing aid or contact lenses, ingrown toenail and scarring as negative outcome controls—where no prior knowledge suggests that an association is expected. Additionally, we tested a pair of negative-exposure controls; we expected that receipt of the influenza vaccine on odd-numbered (n = 605,453) versus even-numbered (n = 571,291) calendar days between 1 March 2020 and 15 January 2021 would be associated with similar risks of the outcomes examined in our analyses. The successful testing of positive outcome controls, negative outcome controls and negative exposure controls may lessen concerns about biases related to study design, covariate selection, analytic approach, outcome ascertainment, unmeasured confounding and other potential sources of latent biases35,36.

All analyses were two-sided. In all analyses, a 95% CI that excluded unity was considered evidence of statistical significance. All analyses were conducted in SAS Enterprise Guide 8.2, and all figures were generated in R version 4.0.4. This study was approved by the VA St. Louis Health Care System Institutional Review Board (protocol no. 1606333).

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The data that support the findings of this study are available from the US Department of Veterans Affairs. VA data are made freely available to researchers behind the VA firewall with an approved VA study protocol. For more information, visit https://www.virec.research.va.gov or contact the VA Information Resource Center at VIReC@va.gov.

Code availability

The analytic code is available at https://github.com/BcBowe3/Breakthrough.

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Long COVID after mild SARS-CoV-2 infection: Persistent heart inflammation might explain heart symptoms

Authors: Goethe University Frankfurt am Main Nature Medicine September 3,2022

After recovering from a SARS-CoV-2 infection, many people complain of persistent heart complaints, such as poor exercise tolerance, palpitations or chest pain, even if the infection was mild and there were no known heart problems in the past. Earlier studies, predominantly among young, physically fit individuals, were already able to show that mild cardiac inflammation can occur after COVID-19. However, the underlying cause of persistent symptoms, and whether this changes over time, was unknown.

A team of medical scientists led by Dr. Valentina Puntmann and Professor Eike Nagel from the Institute for Experimental and Translational Cardiovascular Imaging at University Hospital Frankfurt followed up with 346 people—half of them women—between the age of 18 and 77 years, in each case around 4–11 months after the documented SARS-CoV-2 infection. For this purpose, the team analyzed the study participants’ blood, conducted heart MRIs, and recorded and graded their symptoms using standardized questionnaires.

At the beginning of the study, 73% reported heart problems; for 57% these symptoms persisted 11 months after the SARS-CoV-2 infection. The research team measured mild but persistent heart inflammation that was not accompanied by structural changes in the heart. Blood levels of troponin—a protein that enters the blood when the heart muscle is damaged—were also unremarkable.

Dr. Puntmann, who led the Impression COVID&Heart Study, explains, “The patients’ symptoms match our medical findings. It is important to note that although triggered by the SARS-CoV-2 virus, the post-COVID cardiac inflammatory involvement differs considerably from classic viral myocarditis. Extensive damage of the heart muscle leading to structural heart changes or impaired function are not characteristic at this stage of disease evolution.”

Long COVID after mild SARS-CoV-2 infection: Persistent heart inflammation might explain heart symptoms
Representative magnetic resonance images of a symptomatic patient. (a-f) Late gadolinium enhancement imaging (A, D-F) and Native T1 (B) and T2 (C) mapping measurements of a 57-year-old woman evaluated 201 days after COVID-19 infection. This individual reported dyspnea, palpitations, and chest pain, worsening on minimal exertion. Late gadolinium enhancement imaging allows to visualize regional accumulation of the gadolinium-based contrast agent along the outer rim of the myocardial free wall (red arrows), as well as within the thickened pericardial layers, separated by small amounts of pericardial effusion (blue arrows). Credit: Nature Medicine (2022). DOI: 10.1038/s41591-022-02000-0

The clinical picture is more reminiscent, she says, of the findings in chronic diffuse inflammatory syndromes such as autoimmune conditions. “Although most likely driven by a virus-triggered autoimmune process, a lot more research is needed in order to understand the underlying pathophysiology. Similarly, the long-term effects of cardiac inflammation following a mild COVID infection need to be clarified in future studies.”

Because the study is restricted to a selected group of individuals who took part because they had symptoms, the prevalence of findings cannot be extrapolated to the population as a whole. The study appears in Nature Medicine.

WHO report: 17 million in EU may have suffered long COVID-19

SEPTEMBER 13, 2022 Journal information:Nature Medicine

New research suggests at least 17 million people in the European Union may have experienced long COVID-19 symptoms during the first two years of the coronavirus pandemic, with women more likely than men to suffer from the condition, the World Health Organization said Tuesday.

The research, conducted for the WHO/Europe, was unclear on whether the symptoms that linger, recur or first appear at least one month after a coronavirus infection were more common in vaccinated or unvaccinated people. At least 17 million people met the WHO’s criteria of long COVID-19—with symptoms lasting at least three months in 2020 and 2021, the report said.

“Millions of people in our region, straddling Europe and Central Asia, are suffering debilitating symptoms many months after their initial COVID-19 infection,” said Hans Henri P. Kluge, WHO Regional Director for Europe, during a conference in Tel Aviv.

The modeling also suggests that women are twice as likely as men to experience long COVID-19, and the risk increases dramatically among severe infections needing hospitalization, the report said. One-in-three women and one-in-five men are likely to develop long COVID-19, according to the report.

“Knowing how many people are affected and for how long is important for health systems and government agencies to develop rehabilitative and support services,” said Christopher Murray, director of the Institute for Health Metrics and Evaluation, which conducted the research for the WHO.

The research, which represents estimates and not actual numbers of affected people, tracks with some other recent studies on the constellation of longer-term symptoms after coronavirus infections.

A U.S. study of veterans published in Nature Medicine in May provided fresh evidence that long COVID-19 can happen even after breakthrough infections in vaccinated people, and that older adults face higher risks for the long-term effects. The study showed that about one-third who had breakthrough infections exhibited signs of long COVID.

A separate report from the Centers for Disease Control and Prevention found that up to a year after an initial coronavirus infection, 1 in 4 adults aged 65 and older had at least one potential long COVID-19 health problem, compared with 1 in 5 younger adults.

Most people who have COVID-19 fully recover. But the WHO in Europe report on Tuesday estimated that 10% to 20% develop mid- and long-term symptoms such as fatigue, breathlessness and cognitive dysfunction.

First Diagnostic Test for Long Covid, Detecting Spike Protein in Blood, to Launch in September. Or is it ‘Long Vaccine’?

Authors{ WILL JONES 3 SEPTEMBER 2022 

The first diagnostic designed to identify patients with Long Covid has received CE-IVD marking in Europe, meaning it is ready for its formal launch in countries accepting the designation this month. It works by looking for “patterns of inflammatory marker expression” in the blood, and in particular for the Covid spike protein persisting in white blood cells. Business Wire has the story.

The simple blood test can help to objectively diagnose patients suffering from Post-Acute Sequelae of COVID-19 (PASC), commonly known as Long Covid. Developed by IncellDx, the test will be available to prescribers and patients in September through one of the world’s largest providers of diagnostic services.

A CE Mark indicates that the incellKINE Long Covid In Vitro Diagnostic fulfills the requirements of relevant European product directives and meets all the requirements of the relevant recognised European harmonised performance and safety standards…

The CE marking is supported by data from a validation study conducted by one of the world’s largest providers of diagnostic services, showing the test provides greater than 90% accuracy across Covid strains. The test was developed based on clinical studies published in the peer reviewed journal Frontiers in Immunology, which showed that IncellDx researchers generated credible, objective disease scores for Long Covid using machine learning and artificial intelligence to measure and analyse sets of inflammatory markers called cytokines and chemokines. The studies also demonstrated that patients with previous COVID-19 infection and lingering symptoms were found to have a distinct immunologic profile characterised by patterns of inflammatory marker expression. In a subsequent publication, IncellDx found SARS CoV-2 S1 spike protein in monocytic reservoirs of Long Covid patients up to 15 months after acute infection. These papers can be found here and here.

Patterson added, “Long Covid presents a significant diagnostic and treatment challenge for patients. Many of the symptoms that are associated with long Covid, including fatigue, brain fog, shortness of breath, insomnia, and a wide range of cardiovascular issues, can easily be mistaken for other conditions like post-Lyme, ME-CFS, Fibromyalgia, or even the common cold. Having an effective – and importantly an objective – tool to diagnose the condition is absolutely essential. An objective test that can detect immune signatures specific to Long Covid is vital for effective diagnosis and to enable patients to seek effective treatment.”

Patients who have or think they may have Long Covid can learn more and register for a test here.

One question is how it will distinguish Long Covid from ‘Long Vaccine’. The same research team behind this test also investigated whether vaccination produced a similar syndrome characterised by lingering spike protein, immune inflammation and the typical symptoms. They found it did: spike protein persistence from vaccination appeared, they said, to be a “major contributor” of symptoms similar to Long Covid post-vaccination. Further, given that the spike protein “alone delivered by vaccination can cause similar pathologic features”, they concluded it may be a “major contributor” of Long Covid symptoms post-infection as well. In other words, Long Covid after infection may be being caused or prolonged by spike protein from the vaccine rather than the infection. It’s not clear if the new diagnostic test will distinguish between these causes (or if that’s possible).

A Key to Long Covid Is Virus Lingering in the Body, Scientists Say

Virus remaining in some people’s bodies for a long time may be causing longer-term complications, recent research suggests

Authors:  Sumathi Reddy Sept. 8, 2022 The Wall Street Journal

The virus that causes Covid-19 can remain in some people’s bodies for a long time.  A growing number of scientists think that lingering virus is a root cause of long Covid.

New research has found the spike protein of the SARS-CoV-2 virus in the blood of long Covid patients up to a year after infection but not in people who have fully recovered from Covid. Virus has also been found in tissues including the brain, lungs, and lining of the gut, according to scientists and studies 

The findings suggest that leftover reservoirs of virus could be provoking the immune system in some people, causing complications such as blood clots and inflammation, which may fuel certain long Covid symptoms, scientists say. 

A group of scientists and doctors are joining forces to focus research on viral persistence and aim to raise $100 million to further the search for treatments. Called the Long Covid Research Initiative, the group is run by the PolyBio Research Foundation, a Mercer Island, Wash., based nonprofit focused on complex chronic inflammatory diseases. 

“We really want to understand what’s at the root of [long Covid] and we want to focus on that,” says Amy Proal, a microbiologist at PolyBio and the initiative’s chief scientific officer. Dr. Proal has devoted her career to researching chronic infections after developing myalgic encephalomyelitis/chronic fatigue syndrome, an illness that shares similar symptoms with long Covid, in her 20s.  She has mostly recovered now but has symptoms she manages.

Three long Covid patients, frustrated at the lack of answers and treatments, have helped connect researchers. 

“Long Covid is this really incredible emergency,” says Henry Scott-Green, one of the patients, a 28-year-old in London who says brain fog, extreme fatigue and other debilitating long Covid symptoms prevented him from resuming full-time work as a product manager, though he plans to return soon. “We’re really trying to run really efficiently and cut out as many layers of bureaucracy as possible.”

So far, the group says it has received a pledge of $15 million from Balvi, an investment and direct giving fund established by Vitalik Buterin, the co-creator of the cryptocurrency platform Ethereum. een says debilitating long Covid symptoms have prevented him from resuming full-time work.

Among the strongest evidence of viral persistence in long Covid patients is a new study by Harvard researchers published Friday in the journal of Clinical Infectious Diseases. Researchers detected the spike protein of the SARS-CoV-2 virus in a large majority of 37 long Covid patients in the study and found it in none of 26 patients in a control group.

Patients’ blood was analyzed up to a year after initial infection, says David R. Walt, a professor of pathology at Brigham and Women’s Hospital in Boston and Harvard Medical School and lead researcher of the study. Dr. Walt isn’t currently involved with the long Covid initiative. 

A year after infection, some patients had levels of viral spike protein that were as high as they did earlier in their illness, Dr. Walt says. Such levels long after initial infection suggest that a reservoir of active virus is continuing to produce the spike protein because the spike protein typically doesn’t have a long lifetimehe adds.

Dr. Walt plans to test antivirals such as Paxlovid or remdesivir to see if the drugs help clear the virus and eliminate spike protein from the blood.  He says it’s possible that for some people, the normal course of medication isn’t enough to clear the virus. Such cases may require “a much longer exposure to these antivirals to fully clear,” says Dr. Walt.

One of the research group’s goals is to find a way for people to identify whether they continue to have the virus in their bodies. There is no easy way to determine this now. 

Long Covid patients experience such a wide range of long-term symptoms that scientists think there is likely more than one cause, however. Some cases may be fueled by organ damage, for instance. 

Yet consensus is growing around the idea that lingering virus plays a significant role in long Covid. Preliminary research from immunologist Akiko Iwasaki’s laboratory at Yale University documented T or B cell activity in long Covid patients’ blood, suggesting that patients’ immune systems are continuing to react to virus in their bodies. Dr. Iwasaki is a member of the new initiative. 

In a 58-person study published in the Annals of Neurology in March, University of California, San Francisco researchers also found SARS-CoV-2 proteins circulating in particles in long Covid patients’ blood, especially in those with symptoms such as fatigue and trouble concentrating.

Now, the group is completing a study using imaging techniques and tissue biopsies to detect persistent virus or reactivation of other viruses in tissue. It also is looking at T-cell immune responses in tissues and whether they correlate with symptoms. 

Some people may harbor the virus and don’t have long-term symptoms, says Timothy Henrich, an associate professor of medicine at UCSF involved with the study and a member of the long Covid initiative. For others, lingering virus may produce problems.

“I think there’s a real amount of mounting evidence that really suggests that there is persistent virus in some people,” says Dr. Henrich.

Blood-clotting imbalance persists in Long COVID, research finds

Date: :August 23, 2022Source:RCSI

Summary:

New research from RCSI University of Medicine and Health Sciences has provided greater insight into the causes of Long COVID syndrome.

The findings, which further investigate the link between Long COVID and blood clotting, have been published in the Journal of Thrombosis and Haemostasis.

Long COVID syndrome is a broad collection of symptoms including shortness of breath, fatigue and reduced physical fitness that can continue for many months after initial infection with COVID-19. Understanding is limited about why these symptoms persist in some patients but not others, and the novel syndrome remains a considerable clinical challenge for both doctors and patients alike.

To gain a new understanding of what causes Long COVID, researchers at RCSI studied patients in Ireland with symptoms of Long COVID, and saw that the body’s blood-clotting and immune systems can remain tipped out of balance long after the initial infection.

The team of researchers, led by Professor James O’Donnell at the RCSI School of Pharmacy and Biomolecular Sciences with Dr Helen Fogarty as Clinical Fellow, analysed blood from 50 patients with Long COVID syndrome up to 12 weeks post infection with the COVID-19 virus. They compared the samples to ‘controls’, blood from healthy people who did not have Long COVID syndrome.

The study found that the blood of patients with Long COVID syndrome had higher levels of a blood-clotting booster called von Willebrand Factor (VWF), and lower levels of a protein that normally breaks down VWF, called ADAMTS13. Their analysis also suggests that blood vessels were still being damaged long after the initial infection, and that specific cells of the immune system were at abnormal levels in patients with Long COVID.

“In this study, we examined 50 patients with symptoms of Long COVID syndrome. We saw that, in patients with Long COVID, the normally finely tuned balance of pro- and anti-clotting mechanisms were tipped in favour of blood clotting,” said Dr Helen Fogarty, Health Research Board Irish Clinical Academic Training (ICAT) Programme Fellow and lead author on the paper. “Our analysis also suggests that abnormal clotting and disturbed immunity go hand in hand in Long COVID. Together, these findings may help explain some of the symptoms of Long COVID syndrome.”

Commenting on the study, Professor James O’Donnell said: “Extensive research has been carried on the dangerous clotting observed in patients with acute severe COVID-19 infection, and we now understand a lot more about how and why these deadly clots occur. In this study, we put the focus on Long COVID syndrome, as so much less is known about this persistent illness which is affecting millions of people worldwide.”

The study was carried out by clinical colleagues at St James’s Hospital and researchers at RCSI as part of the Irish COVID-19 Vasculopathy Study (ICVS) collaboration, which includes scientific researchers in RCSI, Trinity College Dublin and University College Dublin as well as clinical partners in St James’s, St Vincent’s and Beaumont Hospitals. The ICVS is supported by a Health Research Board COVID-19 Rapid Response award (COV19-2020-086), and a philanthropic grant from the 3M Foundation to RCSI in support of COVID-19 research.

Journal Reference:

  1. Helen Fogarty, Soracha E. Ward, Liam Townsend, Ellie Karampini, Stephanie Elliott, Niall Conlon, Jean Dunne, Rachel Kiersey, Aifric Naughton, Mary Gardiner, Mary Byrne, Colm Bergin, Jamie M. O’Sullivan, Ignacio Martin‐Loeches, Parthiban Nadarajan, Ciaran Bannan, Patrick W. Mallon, Gerard F. Curley, Roger J. S. Preston, Aisling M. Rehill, Ross I. Baker, Cliona Ni Cheallaigh, James S. O’Donnell, Niamh O’Connell, Kevin Ryan, Dermot Kenny, Judicael Fazavana. Sustained VWF‐ADAMTS‐13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunctionJournal of Thrombosis and Haemostasis, 2022; DOI: 10.1111/jth.15830

Cite This Page: MLA APAChicago RCSI. “Blood-clotting imbalance persists in Long COVID, research finds.” ScienceDaily. ScienceDaily, 23 August 2022. <www.sciencedaily.com/releases/2022/08/220823095434.htm>.