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Three-year outcomes of post-acute sequelae of COVID-19

Cumulative death rate

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to long-term health effects in nearly every organ system, collectively referred to by the patient-coined term Long Covid1,2,3,4,5,6,7,8,9,10,11,12,13,14. Studies following infected individuals for 1 year and 2 years described risk trajectories for many conditions1,3,4,5,6,7,8,9,10,11,12,13,15,16,17,18,19. Risks for some conditions abate after the first year after infection, but risks for many conditions persist at 2 years after initial infection, especially among individuals who were hospitalized for coronavirus disease 2019 (COVID-19) during the acute phase of illness20. About 25% of the burden of the 2-year cumulative burden of disability and disease due to SARS-CoV-2 emanates from the second year after initial infection20. However, studies with longer follow-up times are limited21. It is unclear whether and to what extent risks remain in the third year after infection and whether new latent risks (that have not yet been observed) become apparent in the third year after infection.

Accordingly, we undertook a comprehensive assessment of the risks and burdens of post-acute sequelae of COVID-19 (PASC) across care settings of the acute infection—both non-hospitalized and hospitalized individuals—in the 3 years after infection. Addressing this knowledge gap is important to deepen understanding of the post-acute and long-term health trajectories of people who had SARS-CoV-2 infection and will inform care of people with these conditions.

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Plasma-based antigen persistence in the post-acute phase of COVID-19

SARS-CoV-2 Antiigen

Persistent symptoms among some individuals who develop COVID-19 have led to the hypothesis that SARS-CoV-2 might, in some form or location, persist for long periods following acute infection.

 Studies on SARS-CoV-2 persistence to date, however, have been limited by small and non-representative study populations, short durations since acute infection, unclear documentation of vaccination and reinfection histories, and the absence of a true negative comparator group to assess assay specificity (appendix p 2). To address these limitations, we evaluated the presence of SARS-CoV-2 antigens in once-thawed plasma from a well characterised group of 171 adults (appendix pp 3, 9) at several timepoints in the 14 months following RNA-confirmed SARS-CoV-2 infection, most of whom were studied before vaccination or reinfection (so-called pandemic-era participants).

 To understand the specificity of our findings, we compared them to 250 adults (appendix pp 3, 9) whose plasma was collected before 2020, who, by definition, were not infected with SARS-CoV-2 (pre-pandemic era). We used the Simoa (Quanterix) single molecule array detection platform to measure SARS-CoV-2 spike, S1, and nucleocapsid antigens (appendix p 4).

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Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition

Analysis Immune Response

With an estimated 65 million individuals affected by post-COVID-19 conditions (also known as long COVID), non-invasive biomarkers are direly needed to guide clinical management. To address this pressing need, we used blood transcriptomics in a general practice-based case-control study. Individuals with long COVID were diagnosed according to WHO criteria, and validated clinical scales were used to quantify patient-reported outcomes.

 Whole blood samples were collected from 48 individuals with long COVID and 12 control individuals matched for age, sex, time since acute COVID-19, severity, vaccination status, and comorbidities (appendix 1 p 2). Digital transcriptomic analysis was performed using the nCounter (Nanostring Technologies, Seattle, WA, USA) platform, as described for critical COVID-19.

 Consequently, 212 genes were identified to be differentially expressed between individuals with long COVID and controls (figure A), of which 70 remained significant after adjustment for false discovery rate correction (appendix 1). Several viral RNAs were upregulated: nucleocapsid, ORF7a, ORF3a, Mpro (a nirmatrelvir plus ritonavir [Paxlovid] target), and antisense ORF1ab RNA. Specifically, the upregulation of antisense ORF1ab RNA suggests ongoing viral replication. SARS-CoV-2-related host RNAs (ACE2/TMPRSS2 receptors, DPP4/FURIN proteases) and RNAs prototypical for memory B-cells and platelets

 were also upregulated (figure A). Multivariable logistic regression identified antisense SARS-CoV-2 and FYN RNA concentrations as independent predictors of long COVID (corrected for age and sex; appendix 1 p 2). Receiver operating characteristic curve analysis showed significant discrimination (area under curve [AUC] 0·94, 95% CI 0·86–1·00) between individuals with long COVID (n=48) and controls (n=12), with 93·8% sensitivity and 91·7% specificity (figure B). 

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Solving the Puzzle of Long Covid

Long Covid provides an opportunity to understand 

how acute infections cause chronic disease

More than 4 years into the global COVID-19 pandemic, widespread infection with severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has left millions of people around the world with Long Covid, which describes the constellation of post-acute and long-term adverse health effects caused by the infection. Evidence generated by the scientific community—with formidable contributions from patient-led research teams—has provided a thorough understanding of the epidemiology and clinical manifestations of Long Covid. Understanding the biologic underpinnings of this disease is also improving, along with evidence that vaccination and antivirals can help prevent it. Yet despite this progress, prevention efforts have stalled, there is uncertainty about governments’ long-term commitment to address research needs in this area, and there has yet to be a treatment option validated with randomized controlled trials (RCTs).
Long Covid can manifest in people across the life span (from children to older adults) and across race and ethnicity, sex, and baseline health status. It is a complex, nonmonolithic multisystemic disease with sequelae across almost all organ systems. 

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Symptoms of Long Covid
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Postacute Sequelae of SARS-CoV-2 in Children

PASC in children


The coronavirus disease 2019 (COVID-19) pandemic has caused significant medical, social, and economic impacts globally, both in the short and long term. Although most individuals recover within a few days or weeks from an acute infection, some experience longer lasting effects. Data regarding the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) in children, or long COVID, are only just emerging in the literature. These symptoms and conditions may reflect persistent symptoms from acute infection (eg, cough, headaches, fatigue, and loss of taste and smell), new symptoms like dizziness, or exacerbation of underlying conditions. Children may develop conditions de novo, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune conditions and multisystem inflammatory syndrome in children. This state-of-the-art narrative review provides a summary of our current knowledge about PASC in children, including prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes, as well as a conceptual framework for PASC based on the current National Institutes of Health definition.

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Long-COVID signatures identified in huge analysis of blood proteins

Long Covid Couch

Researchers have developed a computational model that predicts how likely a person is to develop long COVID, based on an analysis of more than 6,500 proteins found in blood.

In a study published on 18 January in Science1, the team compared blood samples from people who tested positive for COVID-19 with ones from healthy adults, and found notable differences in the composition of proteins in people with long COVID, those who recovered and those who were never infected.

The analysis suggests that proteins involved in immune responses, blood clotting and inflammation could be key biomarkers in diagnosing and monitoring long COVID, which affects an estimated 65 million people worldwide.

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Long Covid-19 Foundation

Paving the way to a world, where no life is lost or ruined by Coronavirus.

Long Covid Foundation

For some people, coronavirus (COVID-19) can cause symptoms that last weeks or months after the infection has gone. There are two stages to what is commonly known as Long COVID:

  • Ongoing symptomatic COVID-19 – symptoms that last 4-12 weeks
  • Post-COVID-19 syndrome – symptoms that last for more than 12 weeks and can’t be explained by another diagnosis

It can affect multiple systems in whole body, and your symptoms can change and come and go over time.  It has been seen that despite how severe or mild covid infection was, people still can develop prolonged symptoms. A wide range of long-term symptoms are reported, among others: chest pain, headache, muscle pain, pins and needles, forgetfulness, depression, loss of smell, persistent cough, shortness of breath, palpitations, diarrhoea, abdominal pain, rash, recurrent fever.
There are many reports from people who feel they do not regain their previous health following COVID-19. Preliminary results from a nationally representative sample survey by the UK Office for National Statistics estimates that around 1 in 10 respondents testing positive for COVID-19 may exhibit symptoms for a period of 12 weeks or longer. Other studies indicate that around a third of people testing positive for SARS-CoV-2 had not returned to their usual state of health when interviewed 3 to 6 weeks after diagnosis. In addition, recent studies found that 30% of COVID-19 patients surveyed still had persistent symptoms after nine months. It should be noted that the majority of patients surveyed (85%) were outpatients with mild illness. Some medical doctors have concluded that Long Covid develops due to not treated COVID-19 or not treated aggressively when this was needed.

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How and why patients made Long Covid

Long Covid Cloud

Patients collectively made Long Covid – and cognate term ‘Long-haul Covid’ – in the first months of the pandemic. Patients, many with initially ‘mild’ illness, used various kinds of evidence and advocacy to demonstrate a longer, more complex course of illness than laid out in initial reports from Wuhan. Long Covid has a strong claim to be the first illness created through patients finding one another on Twitter: it moved from patients, through various media, to formal clinical and policy channels in just a few months. This initial mapping of Long Covid – by two patients with this illness – focuses on actors in the UK and the USA and demonstrates how patients marshalled epistemic authority. Patient knowledge needs to be incorporated into how COVID-19 is conceptualized, researched, and treated.

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Immunology of Long COVID

Long Covid Immunology

Long COVID refers to the long-term health and cognition effects that some people experience following infection with COVID-19. Patients have reported unrelenting fatigue, brain fog, dysautonomia, shortness of breath, and digestive problems, among over 200 symptoms — in some cases requiring frequent or even long-term hospitalization. The Iwasaki Lab is interested in exploring the biological mechanisms underlying these phenotypes — and how future research can harness this knowledge to engineer more effective and specific biomarkers for long COVID.

As researchers continue to examine how such patterns can provide information indicative of long COVID, Iwasaki proposes four possible hypotheses for the condition’s initiation and progression.

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The LongCovid Research Consortium is a scientific collaboration to rapidly and comprehensively study LongCovid.

LongCovid is no longer a mystery. New research is revealing key drivers of the condition, including evidence strongly suggesting that patients with LongCovid do not fully clear the SARS-CoV-2 virus. Instead, the virus may persist in tissue where it continues to provoke the immune system. This could drive a wide range of downstream consequences such as blood clotting, neuroinflammation, and neuropathy. The persistence of SARS-CoV-2 in tissue is called a viral reservoir.

The LongCovid Research Consortium has established a comprehensive research program on LongCovid disease mechanisms, with a focus on viral reservoir. The program includes scientists and clinicians from institutions including Harvard Medical School, University of California San Francisco, the J. Craig Venter Institute, Johns Hopkins, University of Pennsylvania, the Icahn School of Medicine at Mount Sinai, Cardiff University and Yale University.

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Long Covid Action Project (LCAP) is a united, diverse force of non-partisan individuals taking action to end the Long COVID crisis. We demand urgent treatment and support for the Long COVID community by mobilizing public awareness and driving government accountability.

We encourage everyone with or without Long Covid to participate in taking action to help push for an end to the Long Covid crisis. If you have ideas or action items you want to see, please contact us or add your thoughts to the appropriate Long Covid sections in the general Google doc. Volunteer work and donations are always welcome.

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Declare LC a National Emergency
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Experiences of Canadians with long-term symptoms following COVID-19

by Sianne Kuang, Steven Earl, Janine Clarke, Dianne Zakaria, Alain Demers, and Samina Aziz
Release date: December 8, 2023
Long COVID Study

Overview of Study

  • As of June 2023, about two-thirds of Canadian adults reported at least one confirmed or suspected COVID-19 infection, with many reporting more than one infection since the beginning of the pandemic.
  • Multiple infections were more commonly reported among certain racialized groups; Black Canadians were most likely to report multiple infections compared to other racialized groups.
  • About 3.5 million Canadian adults reported experiencing long-term symptoms following a COVID-19 infection; 2.1 million reported they were still experiencing those symptoms as of June 2023. Almost half of those still experiencing symptoms reported they have not seen any improvement in symptoms over time.
  • Among Canadians who were in school or employed and dealing with long-term symptoms, more than 1 in 5 missed days of school or work, missing 24 days on average.
  • About 40% of those with long-term symptoms who sought healthcare about their symptoms reported difficulties with access.
  • Adults with chronic conditions and senior adults were more likely to have been vaccinated in the 6 months prior to June 2023.

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Symptom Prevalence by Severity
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Clinical characteristics of Long COVID patients presenting to a dedicated academic post-COVID-19 clinic in Central Texas

The majority of PASC ( Long COVID) patients in our cohort had mild to moderate acute COVID-19 disease and did not require hospitalization. Most patients experienced ongoing symptoms for the past 10 months, with significant functional impairment, indicating that PASC is a long-term debilitating illness for affected patients. Notably, there was significant symptom overlap between patients, suggesting likely overlapping pathophysiology across PASC. Given the complexity of the diagnosis and treatment of PASC, multispecialty clinics are required to meet the needs of the PASC patient population with the integration of research studies toward a better understanding of the long-term health consequences of PASC and developing evidence-based PASC treatments.

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Long COVID Foundation

Long COVID Will Steal Your Life

At the Long COVID Foundation, our mission is to bring awareness to the public regarding Long COVID & other pandemic-related issues, advocate for better testing, trials, & treatments for Long COVID, and take action in assisting COVID Long Haulers, and others affected by the pandemic, which includes putting forth campaigns to aid in the mitigation of COVID and other actions. We are big believers that COVID Viral Persistence and COVID Spike Persistence should be the main focus of researchers and others.

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Civilian Labor Force - With a Disability, 16 Years and Over (US)

Fred Disability Graph

What is FRED? Short for Federal Reserve Economic Data, FRED is an online database consisting of hundreds of thousands of economic data time series from scores of national, international, public, and private sources. FRED, created and maintained by the Research Department at the Federal Reserve Bank of St. Louis, goes far beyond simply providing data: It combines data with a powerful mix of tools that help the user understand, interact with, display, and disseminate the data. 

The graph shows rising disabilities ststs (updated October 2023) observing over 8,000 workers from June 2008 through October 2023. Look at what happens in 2021, a year after the COVID-19 pandemic started.

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Long COVID quality of life and healthcare experiences in the UK: a mixed method online survey

Long COVID has a severe impact on the ability to live life fully, and strains mental health. The appropriate mechanisms and support services are needed to support those living with long COVID and manage symptom
Long Covid Lived Experience
Long Covid Podcast

Long Covid 19 Podcast

the podcast by and for Long Covid sufferers

Long Covid is estimated to affect at least 1 in 5 people infected with Covid-19. Many of these people were fit & healthy, and many successfully managed other conditions. Some people recover within a few months, but many have been suffering for much, much longer.

Although there is currently no “cure” for Long Covid, and the thousands of people still ill have been searching for answers for a long time, people have recovered. In this series of podcasts, we explore the many things that can be done to help, through a mix of medical experts, researchers, and personal experience from those who know it best – the Long Haulers. 

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Mysteries of Long Covid

Distinct immune, hormone responses shed light on mysteries of long COVID

People who have experienced brain fog, confusion, pain, and extreme fatigue for months or longer after being infected with the COVID-19 virus exhibit different immune and hormonal responses to the virus than those not diagnosed with long COVID, according to a new study by researchers at Yale School of Medicine and Icahn School of Medicine at Mount Sinai.

The discovery of these distinct responses can help scientists for the first time identify the causes — and potentially explore cures — for the often debilitating illness that has afflicted millions of people worldwide. An estimated 7.5% of people infected with the SARS-CoV-2 virus in the U.S. later suffer from long COVID.

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Long COVID: major findings, mechanisms and recommendations

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems.

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Articles and Research on Long COVID

The Covid Safe Network has posted numerous articles and Research studies on Long Covid. They also include several videos on the Immunology of Long Covid and Long Covid and Microclots. This is a working document that is updated with new submissions so be sure to check back or bookmark the site.

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What are we learning about Long Covid? Should the risk of chronic illness change what precautions we take?

Long Covid Learning collects research from scientists worldwide and summarizes the findings to make takeaways more accessible to those outside the research community. Study summaries can be shared as links or images in messages and social media.

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Long Covid Kids

We believe all children should be able to thrive and look forward to a positive future.

That is why we represent and support children and young people living with Long Covid and related illnesses and the parents and caregivers that look after them

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Long COVID or Post-COVID Conditions

Some people who have been infected with the virus that causes COVID-19 can experience long-term effects from their infection, known as Long COVID or Post-COVID Conditions (PCC). Long COVID is broadly defined as signs, symptoms, and conditions that continue or develop after acute COVID-19 infection. 

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Long Covid: symptoms, tests, treatment and support

Updated 10 May 2023

We look at the symptoms of long Covid, how long it lasts, and what tests and treatments are available.

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What if SARS-CoV-2 continues to infect us even after the initial symptoms fade?

A recent study from the University of California San Francisco (UCSF) used advanced imaging techniques to identify persistent T lymphocyte activation in many parts of the body up to 2.5 years after acute SARS‑CoV‑2 infection.

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A network supporting and conducting research into the Post-COVID Condition (PCC)

Our aim is to create a clear and organized national plan. This plan will help combine research with patient care and education about Post-COVID Conditions (PCC). We want to understand PCC better, find markers in the body, and identify ways to treat it. We also want to look at how different racial and Indigenous groups are affected by PCC and improve access to care and recovery for PCC patients.

Visit Long COVID Web

Post COVID-19 condition (long COVID)

Post COVID-19 condition is when the symptoms of COVID-19 persist for more than 12 weeks after the infection. It’s also known as long COVID, and can affect both adults and children.

You can show symptoms of post-COVID-19 condition even if you:

  • weren’t formally tested and diagnosed with COVID-19
  • only had mild to moderate symptoms when you had COVID-19
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Why viral reservoirs are a prime suspect for long COVID sleuths

Brent Palmer’s first inkling about long COVID started in the early days of the pandemic, before the term “long COVID” even existed.

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Long Covid: MRI scans reveal new clues to symptoms

People living with long Covid after being admitted to hospital are more likely to show some damage to major organs, according to a new study.

MRI scans revealed patients were three times more likely to have some abnormalities in multiple organs such as the lungs, brain and kidneys.

Researchers believe there is a link with the severity of the illness.

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Long COVID (World Health Network)

COVID infections cause damage to the body resulting in brain fog, heart issues, and fatigue, and events like heart attacks and strokes that can be fatal. This occurs even in those who have mild or asymptomatic infections and in young and healthy individuals.

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Long Covid Cognitive Difficulties

Cognitive-linguistic difficulties in adults with Long COVID: A follow-up study

he COVID-19 pandemic has undoubtedly been the global health challenge of our time. But aside from the large number of deaths caused by SARS-CoV-2 (the virus that causes COVID-19), an even greater number of people with long-term debilitating illness could yet be the legacy of this pandemic. As we learn more about the pathophysiological effects of SARS-CoV-2 it is clear that a large burden of cognitive impairment exists alongside physical symptoms in people with Long COVID. 

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Long Covid Action Project (LCAP) is a united, diverse force of non-partisan individuals taking action to end the Long COVID crisis. We demand urgent treatment and support for the Long COVID community by mobilizing public awareness and driving government accountability.

Take Action

All Long COVID

Long COVID: pathophysiological factors and abnormalities of coagulation

Long COVID is a multisystem disease with debilitating symptoms, which has had a profound impact on society and the global economy. There are several potential pathophysiological mechanisms, some of which may be causative and others likely to be epiphenomena. These include viral factors, host factors, and downstream impacts. These mechanisms interact with the vascular endothelium to induce a persistent thrombotic endothelialitis with systemic hypercoagulability. This may promote the formation of fibrinaloid microclots, platelet hyperactivation, and endothelial dysfunction, which can lead to various clotting pathologies. Currently, there are no definitive treatments for the condition.

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