new research on long haul covid

Long Covid explanation in new study possibly paves way for tests and treatments

Scientists have identified a persistent change in a handful of blood proteins in people with long Covid that indicates that an important part of their immune system remains on high alert for months after an acute infection.

The findings , published Thursday in the journal Science, could help explain what causes the persistent fatigue, brain fog and other debilitating symptoms of long Covid , as well as pave the way for diagnostic tests and potentially, a long-awaited treatment, experts say.

The study followed 113 Covid patients for up to one year after they were first infected, along with 39 healthy controls. At the six-month mark, 40 patients had developed long Covid symptoms .

Repeated blood samples turned up important differences in their blood: A group of proteins indicated that a part of the body’s immune system called the complement system remained activated long after it should have returned to normal.

“When you have a viral or bacterial infection , the complement system becomes activated and binds to these viruses and bacteria and then eliminates them,” said Dr. Onur Boyman, a professor of immunology at the University of Zurich in Switzerland and one of the study’s investigators. The system then returns to its resting state, where its regular job is to clear the body of dead cells, he said.

But if the complement system remains in its microbe-fighting state after the viruses and bacteria are eliminated, “it starts damaging healthy cells,” he said.

“These can be endothelial cells that line the inner layers of blood vessels, the cells of the blood itself, and cells in different organs, like the brain or the lungs,” he continued. The result is tissue damage and microclots in the blood.

Previous studies have documented blood clotting and tissue damage in people with long Covid. “But this research gets at the molecular mechanism of how that might be initiated,” said Akiko Iwasaki, a professor of immunobiology and molecular, cellular and developmental biology at the Yale School of Medicine, who was not involved with the new study.

Tissue damage along with blood clots can lead to the disabling symptoms of long Covid, including an intolerance to exercise.

During exercise, the heart pumps more blood and agitates the endothelial cells inside blood vessels, which are everywhere in the body, Boyman said.

“In healthy people, normal endothelial cells can take these changes, but the inflamed endothelial cells in long Covid patients cannot,” he said.

Iwasaki noted that microclots can reduce the level of oxygen and nutrients delivered to different organs.

“If your brain, for example, isn’t getting enough oxygen, obviously there will be a lot of issues with memory, brain fog and fatigue,” she said.

A possible path to tests and treatments

A little more than 14% of adults in the United States report ever having experienced long Covid, according to the most recent data from the U.S. Census Bureau’s Household Pulse Survey .

Dr. Monica Verduzco-Gutierrez, chair of rehabilitation medicine at the University of Texas Health Science Center at San Antonio and head of its long Covid clinic, praised the new study.

“Understanding the mechanisms of long Covid is how we’re going to figure out treatments,” she said.

Other studies have also identified potential mechanisms. In one study , published in the October issue of the journal Cell, researchers suggested that remnants of the virus lingering in the gut of long Covid patients triggered reductions in the neurotransmitter serotonin. Lower serotonin levels, they said, could explain some neurological and cognitive symptoms. Another study , published in the journal Nature in September by Iwasaki and her colleagues, found that long Covid patients had significantly lower levels of the hormone cortisol than other Covid patients and healthy controls. Cortisol helps people feel alert and awake.

Verduzco-Gutierrez, Iwasaki and Boyman agree that the new research points the way toward developing diagnostic tests and treatment by focusing on the proteins of the complement system.

However, Boyman and his colleagues used cutting-edge, complicated methods for detecting the differences in these proteins that could not be used in a routine diagnostic lab.

“We need companies already active in diagnostics that have sufficient manpower and financial power” to develop a simplified test, he said.

Once a test is developed, or with rigorous screening for long Covid patients, pharmaceutical companies could begin clinical trials of potential treatments, Boyman said. Drugs already exist to modulate and inhibit the complement system for very rare immune diseases that affect the kidneys, muscles or nervous system, and they could be tested in long Covid patients, he said.

New drugs could also be developed, Iwasaki said.

“I think there are a lot of things that we can try in the future,” she said. But first, the results of this study need to be replicated, as with any research, she added.

Verduzco-Gutierrez said she would like to see any future studies follow patients for a longer period of time. “What about people who have had long Covid for three years? We don’t know what their blood looks like,” she said.

Barbara Mantel is an NBC News contributor. She is also the topic leader for freelancing at the Association of Health Care Journalists, writing blog posts, tip sheets and market guides, as well as producing and hosting webinars. Barbara’s work has appeared in CQ Researcher, AARP, Undark, Next Avenue, Medical Economics, Healthline, Today.com, NPR and The New York Times.

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Long COVID symptoms linked to inflammation

At a glance.

Prolonged inflammation after SARS-CoV-2 infections caused permanent damage to lungs and kidneys, affected the brain, and correlated with behavioral changes in hamsters.
The results suggest a mechanism for the symptoms of Long COVID in people.

Older man holding his head with one hand and a tissue in the other

The effects of COVID-19 can persist long after the initial symptoms of the illness are gone. These effects, called post-acute sequelae of COVID-19 (or PASC), can include brain fog, fatigue, headaches, dizziness, and shortness of breath. Long COVID—when symptoms last weeks or months after the acute infection has passed—affects about 2.5% of COVID patients. While patients who were hospitalized are more susceptible, even those with mild cases can experience Long COVID.

A research team led by Drs. Benjamin tenOever at the NYU Grossman School of Medicine and Venetia Zachariou at the Icahn School of Medicine at Mount Sinai set out to understand the underlying biology of Long COVID. The researchers, who were supported in part by NIH, studied the golden hamster, a widely used small animal model for respiratory infections. The hamsters were exposed to SARS-CoV-2 via their nostrils. For comparison, another group was exposed to a flu virus, influenza A. Various samples were taken for analysis after 3, 14, and 31 days of infection.

Tissues from human donors who had COVID-19 at the time of death or had recovered from COVID-19 but died from other causes were also sampled and analyzed. Results appeared on June 7, 2022, in Science Translational Medicine.

Both SARS-CoV-2 and influenza A infections were largely cleared within two weeks, similar to the course of recovery in humans. Following SARS-CoV-2 infection, however, animals showed much more extensive lung damage and slower recovery than those exposed to influenza A. Those exposed to SARS-CoV-2 also had more kidney damage.

When the scientists sampled different parts of hamster brains to analyze gene activity, they found that SARS-CoV-2 had unique effects on the hamster olfactory system—the parts of the nose and brain responsible for smell. The olfactory epithelium, the lining inside the nose, showed signs of extensive inflammation long after the virus could be detected. SARS-CoV-2 also caused high levels of inflammation in the olfactory bulb, a part of the brain involved in processing smell as well as in emotion and learning. Inflammation in these areas persisted long after the infection was cleared.

Interestingly, chronic inflammation in the olfactory system correlated with behavioral changes in the hamsters thought to reflect mood disorders like depression and anxiety. Although olfactory bulb tissue from people who recovered from COVID-19 and died of other causes is difficult to obtain, the few samples studied were comparable to that of the hamsters. This suggests that the inflammation seen in the hamsters may explain the mechanism responsible for symptoms of Long COVID in people. Further research is needed to fully understand the link between brain inflammation, brain activity, and behavioral changes.

“[T]his study suggests that the molecular mechanism behind many Long COVID-19 symptoms stems from this persistent inflammation while describing an animal model close enough to human biology to be useful in the design of future treatments,” tenOever says.

—by Larisa Gearhart-Serna, Ph.D.

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Study identifies risk factors for long-haul COVID disease in adults

Lynda De Widt

Study Findings

"We found that patients with severe COVID-19 symptoms were more likely to have long-haul COVID than those who had mild symptoms," says Bala Munipalli, M.D., an internist at Mayo Clinic in Florida and co-senior author of the study. "A majority of these were women who had been hospitalized, suffered from psychological impacts from COVID-19 such as anxiety and depression, and required more than one month to return to their normal activities after the illness."

The average age of the respondents in the study was 54 and most were women, including 57% of the patients surveyed who reported severe symptoms; 60% with mild symptoms; and 65% with moderate symptoms. Most patients (92%) with mild symptoms were able to resume their usual schedules within four weeks after COVID-19 infection, but 23% of these patients with mild acute infection developed long-haul COVID. Significantly more (37.4%) patients with severe symptoms were hospitalized than those with mild (0.9%) or moderate symptoms (4.8%). Hospitalized patients also reported having persistent symptoms of long-haul COVID (67%), needing a month or more to resume their usual activities, missing work for at least three weeks, and having negative psychological side effects.

Most respondents in the study reported long-haul COVID symptoms that lasted three to six months, with those symptoms ranging in severity. The most common symptoms in the study group were fatigue, loss of smell, altered taste, shortness of breath and poor sleep.

More to learn

"The inability to resume normal activities within one month after acute COVID-19 may be a predictive factor for long-haul COVID. As we continue to study this disease, we hope to gain a better understanding of who is susceptible to it, the symptoms that remain persistent, and how to best manage these patients in the early course of their illness," says Dr. Munipalli. "Additional studies may help guide the standardization of future assessment tools to evaluate impairment and also provide valuable information to employers, educators, policymakers and patients."

The researchers note that a multidisciplinary approach to long-haul COVID is needed and that healthcare personnel should recognize key symptoms, obtain a careful medical history and physical examination, as well as pay close attention to comorbid medical conditions in patients with persistent symptoms.

Dr. Munipalli says her team plans additional research focusing on treatments for long-haul COVID.

Other Mayo Clinic researchers on this paper include Abd Moain Abu Dabrh, M.B., B.Ch., M.S. ; Dacre Knight, M.D. ; Ilana Logvinov, M.D.; Stefan Paul; Troy Delaney, Yaohua Ma; Zhuo Li; and Ravindra Ganesh, M.B.B.S., M.D.

Mayo Clinic in Florida opens downtown Jacksonville site focused on education, research Mayo Clinic expert answers questions about the new COVID-19 vaccine

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Open access
Published: 08 April 2024

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

Felicity Liew 1 na1 ,
Claudia Efstathiou ORCID: orcid.org/0000-0001-6125-8126 1 na1 ,
Sara Fontanella 1 ,
Matthew Richardson 2 ,
Ruth Saunders 2 ,
Dawid Swieboda 1 ,
Jasmin K. Sidhu 1 ,
Stephanie Ascough 1 ,
Shona C. Moore ORCID: orcid.org/0000-0001-8610-2806 3 ,
Noura Mohamed 4 ,
Jose Nunag ORCID: orcid.org/0000-0002-4218-0500 5 ,
Clara King 5 ,
Olivia C. Leavy 2 , 6 ,
Omer Elneima 2 ,
Hamish J. C. McAuley 2 ,
Aarti Shikotra 7 ,
Amisha Singapuri ORCID: orcid.org/0009-0002-4711-7516 2 ,
Marco Sereno ORCID: orcid.org/0000-0003-4573-9303 2 ,
Victoria C. Harris 2 ,
Linzy Houchen-Wolloff ORCID: orcid.org/0000-0003-4940-8835 8 ,
Neil J. Greening ORCID: orcid.org/0000-0003-0453-7529 2 ,
Nazir I. Lone ORCID: orcid.org/0000-0003-2707-2779 9 ,
Matthew Thorpe 10 ,
A. A. Roger Thompson ORCID: orcid.org/0000-0002-0717-4551 11 ,
Sarah L. Rowland-Jones 11 ,
Annemarie B. Docherty ORCID: orcid.org/0000-0001-8277-420X 10 ,
James D. Chalmers 12 ,
Ling-Pei Ho ORCID: orcid.org/0000-0001-8319-301X 13 ,
Alexander Horsley ORCID: orcid.org/0000-0003-1828-0058 14 ,
Betty Raman 15 ,
Krisnah Poinasamy 16 ,
Michael Marks 17 , 18 , 19 ,
Onn Min Kon 1 ,
Luke S. Howard ORCID: orcid.org/0000-0003-2822-210X 1 ,
Daniel G. Wootton 3 ,
Jennifer K. Quint 1 ,
Thushan I. de Silva ORCID: orcid.org/0000-0002-6498-9212 11 ,
Antonia Ho 20 ,
Christopher Chiu ORCID: orcid.org/0000-0003-0914-920X 1 ,
Ewen M. Harrison ORCID: orcid.org/0000-0002-5018-3066 10 ,
William Greenhalf 21 ,
J. Kenneth Baillie ORCID: orcid.org/0000-0001-5258-793X 10 , 22 , 23 ,
Malcolm G. Semple ORCID: orcid.org/0000-0001-9700-0418 3 , 24 ,
Lance Turtle 3 , 24 ,
Rachael A. Evans ORCID: orcid.org/0000-0002-1667-868X 2 ,
Louise V. Wain 2 , 6 ,
Christopher Brightling 2 ,
Ryan S. Thwaites ORCID: orcid.org/0000-0003-3052-2793 1 na1 ,
Peter J. M. Openshaw ORCID: orcid.org/0000-0002-7220-2555 1 na1 ,
PHOSP-COVID collaborative group &

ISARIC investigators

Nature Immunology volume 25 , pages 607–621 ( 2024 ) Cite this article

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Inflammasome
Inflammation
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One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood 1 . Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19

Keith Sacco, Riccardo Castagnoli, … Luigi D. Notarangelo

In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach

Michael Maes, Walton Luiz Del Tedesco Junior, … Andréa Name Colado Simão

Epidemiology, clinical presentation, pathophysiology, and management of long COVID: an update

Sizhen Su, Yimiao Zhao, … Lin Lu

One in ten severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections results in post-acute sequelae of coronavirus disease 2019 (PASC) or long coronavirus disease (COVID), which affects 65 million people worldwide 1 . Long COVID (LC) remains common, even after mild acute infection with recent variants 2 , and it is likely LC will continue to cause substantial long-term ill health, requiring targeted management based on an understanding of how disease phenotypes relate to underlying mechanisms. Persistent inflammation has been reported in adults with LC 1 , 3 , but studies have been limited in size, timing of samples or breadth of immune mediators measured, leading to inconsistent or absent associations with symptoms. Markers of oxidative stress, metabolic disturbance, vasculoproliferative processes and IFN-, NF-κB- or monocyte-related inflammation have been suggested 3 , 4 , 5 , 6 .

The PHOSP-COVID study, a multicenter United Kingdom study of patients previously hospitalized with COVID-19, has reported inflammatory profiles in 626 adults with health impairment after COVID-19, identified through clustering. Elevated IL-6 and markers of mucosal inflammation were observed in those with severe impairment compared with individuals with milder impairment 7 . However, LC is a heterogeneous condition that may be a distinct form of health impairment after COVID-19, and it remains unclear whether there are inflammatory changes specific to LC symptom subtypes. Determining whether activated inflammatory pathways underlie all cases of LC or if mechanisms differ according to clinical presentation is essential for developing effective therapies and has been highlighted as a top research priority by patients and clinicians 8 .

In this Letter, in a prospective multicenter study, we measured 368 plasma proteins in 657 adults previously hospitalized for COVID-19 (Fig. 1a and Table 1 ). Individuals in our cohort experienced a range of acute COVID-19 severities based on World Health Organization (WHO) progression scores 9 ; WHO 3–4 (no oxygen support, n = 133 and median age of 55 years), WHO 5–6 (oxygen support, n = 353 and median age of 59 years) and WHO 7–9 (critical care, n = 171 and median age of 57 years). Participants were hospitalized for COVID-19 ≥3 months before sample collection (median 6.1 months, interquartile range (IQR) 5.1–6.8 months and range 3.0–8.3 months) and confirmed clinically ( n = 36/657) or by PCR ( n = 621/657). Symptom data indicated 233/657 (35%) felt fully recovered at 6 months (hereafter ‘recovered’) and the remaining 424 (65%) reported symptoms consistent with the WHO definition for LC (symptoms ≥3 months post infection 10 ). Given the diversity of LC presentations, patients were grouped according to symptom type (Fig. 1b ). Groups were defined using symptoms and health deficits that have been commonly reported in the literature 1 ( Methods ). A multivariate penalized logistic regression model (PLR) was used to explore associations of clinical covariates and immune mediators at 6 months between recovered patients ( n = 233) and each LC group (cardiorespiratory symptoms, cardioresp, n = 398, Fig. 1c ; fatigue, n = 384, Fig. 1d ; affective symptoms, anxiety/depression, n = 202, Fig. 1e ; gastrointestinal symptoms, GI, n = 132, Fig. 1f ; and cognitive impairment, cognitive, n = 61, Fig. 1g ). Women ( n = 239) were more likely to experience CardioResp (odds ratio (OR 1.14), Fatigue (OR 1.22), GI (OR 1.13) and Cognitive (OR 1.03) outcomes (Fig. 1c,d,f,g ). Repeated cross-validation was used to optimize and assess model performance ( Methods and Extended Data Fig. 1 ). Pre-existing conditions, such as chronic lung disease, neurological disease and cardiovascular disease (Supplementary Table 1 ), were associated with all LC groups (Fig. 1c–g ). Age, C-reactive protein (CRP) and acute disease severity were not associated with any LC group (Table 1 ).

a , Distribution of time from COVID-19 hospitalization at sample collection. All samples were cross-sectional. The vertical red line indicates the 3 month cutoff used to define our final cohort and samples collected before 3 months were excluded. b , An UpSet plot describing pooled LC groups. The horizontal colored bars represent the number of patients in each symptom group: cardiorespiratory (Cardio_Resp), fatigue, cognitive, GI and anxiety/depression (Anx_Dep). Vertical black bars represent the number of patients in each symptom combination group. To prevent patient identification, where less than five patients belong to a combination group, this has been represented as ‘<5’. The recovered group ( n = 233) were used as controls. c – g , Forest plots of Olink protein concentrations (NPX) associated with Cardio_Resp ( n = 365) ( c ), fatigue (n = 314) ( d ), Anx_Dep ( n = 202) ( e ), GI ( n = 124) ( f ) and cognitive ( n = 60) ( g ). Neuro_Psych, neuropsychiatric. The error bars represent the median accuracy of the model. h , i , Distribution of Olink values (NPX) for IL-1R2 ( h ) and MATN2, neurofascin and sCD58 ( i ) measured between symptomatic and recovered individuals in recovered ( n = 233), Cardio_Resp ( n = 365), fatigue ( n = 314) and Anx_Dep ( n = 202) groups ( h ) and MATN2 in GI ( n = 124), neurofascin in cognitive ( n = 60) and sCD58 in Cardio_Resp and recovered groups ( i ). The box plot center line represents the median, the boundaries represent IQR and the whisker length represents 1.5× IQR. The median values were compared between groups using two-sided Wilcoxon signed-rank test, * P < 0.05, ** P < 0.01, *** P < 0.001 and **** P < 0.0001.

To study the association of peripheral inflammation with symptoms, we analyzed cross-sectional data collected approximately 6 months after hospitalizations. We measured 368 immune mediators from plasma collected contemporaneously with symptom data. Mediators suggestive of myeloid inflammation were associated with all symptoms (Fig. 1c–h ). Elevated IL-1R2, an IL-1 receptor expressed by monocytes and macrophages modulating inflammation 11 and MATN2, an extracellular matrix protein that modulates tissue inflammation through recruitment of innate immune cells 12 , were associated with cardioresp (IL-1R2 OR 1.14, Fig. 1c,h ), fatigue (IL-1R2 OR 1.45, Fig. 1d,h ), anxiety/depression (IL-1R2 OR 1.34. Fig. 1e,h ) and GI (MATN2 OR 1.08, Fig. 1f ). IL-3RA, an IL-3 receptor, was associated with cardioresp (OR 1.07, Fig. 1c ), fatigue (OR 1.21, Fig. 1d ), anxiety/depression (OR 1.12, Fig. 1e ) and GI (OR 1.06, Fig. 1f ) groups, while CSF3, a cytokine promoting neutrophilic inflammation 13 , was elevated in cardioresp (OR 1.06, Fig. 1c ), fatigue (OR 1.12, Fig. 1d ) and GI (OR 1.08, Fig. 1f ).

Elevated COLEC12, which initiates inflammation in tissues by activating the alternative complement pathway 14 , associated with cardioresp (OR 1.09, Fig. 1c ), fatigue (OR 1.19, Fig. 1d ) and anxiety/depression (OR 1.11, Fig. 1e ), but not with GI (Fig. 1f ) and only weakly with cognitive (OR 1.02, Fig. 1g ). C1QA, a degradation product released by complement activation 15 was associated with GI (OR 1.08, Fig. 1f ) and cognitive (OR 1.03, Fig. 1g ). C1QA, which is known to mediate dementia-related neuroinflammation 16 , had the third strongest association with cognitive (Fig. 1g ). These observations indicated that myeloid inflammation and complement activation were associated with LC.

Increased expression of DPP10 and SCG3 was observed in the GI group compared with recovered (DPP10 OR 1.07 and SCG3 OR 1.08, Fig. 1f ). DPP10 is a membrane protein that modulates tissue inflammation, and increased DPP10 expression is associated with inflammatory bowel disease 17 , 18 , suggesting that GI symptoms may result from enteric inflammation. Elevated SCG3, a multifunctional protein that has been associated with irritable bowel syndrome 19 , suggested that noninflammatory disturbance of the brain–gut axis or dysbiosis, may occur in the GI group. The cognitive group was associated with elevated CTSO (OR 1.04), NFASC (OR 1.03) and SPON-1 (OR 1.02, Fig. 1g,i ). NFASC and SPON-1 regulate neural growth 20 , 21 , while CTSO is a cysteine proteinase supporting tissue turnover 22 . The increased expression of these three proteins as well as C1QA and DPP10 in the cognitive group (Fig. 1g ) suggested neuroinflammation and alterations in nerve tissue repair, possibly resulting in neurodegeneration. Together, our findings indicated that complement activation and myeloid inflammation were common to all LC groups, but subtle differences were observed in the GI and cognitive groups, which may have mechanistic importance. Acutely elevated fibrinogen during hospitalization has been reported to be predictive of LC cognitive deficits 23 . We found elevated fibrinogen in LC relative to recovered (Extended Data Fig. 2a ; P = 0.0077), although this was not significant when restricted to the cognitive group ( P = 0.074), supporting our observation of complement pathway activation in LC and in keeping with reports that complement dysregulation and thrombosis drive severe COVID-19 (ref. 24 ).

Elevated sCD58 was associated with lower odds of all LC symptoms and was most pronounced in cardioresp (OR 0.85, Fig. 1c,i ), fatigue (OR 0.80, Fig. 1d ) and anxiety/depression (OR 0.83, Fig. 1e ). IL-2 was negatively associated with the cardioresp (Fig. 1c , OR 0.87), fatigue (Fig. 1d , OR 0.80), anxiety/depression (Fig. 1e , OR 0.84) and cognitive (Fig. 1g , OR 0.96) groups. Both IL-2 and sCD58 have immunoregulatory functions 25 , 26 . Specifically, sCD58 suppresses IL-1- or IL-6-dependent interactions between CD2 + monocytes and CD58 + T or natural killer cells 26 . The association of sCD58 with recovered suggests a central role of dysregulated myeloid inflammation in LC. Elevated markers of tissue repair, IDS and DNER 27 , 28 , were also associated with recovered relative to all LC groups (Fig. 1c–g ). Taken together, our data suggest that suppression of myeloid inflammation and enhanced tissue repair were associated with recovered, supporting the use of immunomodulatory agents in therapeutic trials 29 (Supplementary Table 2 ).

We next sought to validate the experimental and analytical approaches used. Although Olink has been validated against other immunoassay platforms, showing superior sensitivity and specificity 30 , 31 , we confirmed the performance of Olink against chemiluminescent immunoassays within our cohort. We performed chemiluminescent immunoassays on plasma from a subgroup of 58 participants (recovered n = 13 and LC n = 45). There were good correlations between results from Olink (normalized protein expression (NPX)) and chemiluminescent immunoassays (pg ml −1 ) for CSF3, IL-1R2, IL-3RA, TNF and TFF2 (Extended Data Fig. 3 ). Most samples did not have concentrations of IL-2 detectable using a mesoscale discovery chemiluminescent assay, limiting this analysis to 14 samples (recovered n = 4, LC n = 10, R = 0.55 and P = 0.053, Extended Data Fig. 3 ). We next repeated our analysis using alternative definitions of LC. The Centers for Disease Control and Prevention and National Institute for Health and Care Excellence definitions for LC include symptoms occurring 1 month post infection 32 , 33 . Using the 1 month post-infection definition included 62 additional participants to our analysis (recovered n = 21, 3 females and median age 61 years and LC n = 41, 15 females and median age 60 years, Extended Data Fig. 2c ) and found that inflammatory associations with each LC group were consistent with our analysis based on the WHO definition (Extended Data Fig. 2d–h ). Finally, to validate the analytical approach (PLR) we examined the distribution of data, prioritizing proteins that were most strongly associated with each LC/recovered group (IL-1R2, MATN2, NFASC and sCD58). Each protein was significantly elevated in the LC group compared with recovered (Fig. 1h,i and Extended Data Fig. 4 ), consistent with the PLR. Alternative regression approaches (unadjusted regression models and partial least squares, PLS) reported results consistent with the original analysis of protein associations and LC outcome in the WHO-defined cohort (Fig. 1c–g , Supplementary Table 3 and Extended Data Figs. 5 and 6 ). The standard errors of PLS estimates were wide (Extended Data Fig. 6 ), consistent with previous demonstrations that PLR is the optimal method to analyze high-dimensional data where variables may have combined effects 34 . As inflammatory proteins are often colinear, working in-tandem to mediate effects, we prioritized PLR results to draw conclusions.

To explore the relationship between inflammatory mediators associated with different LC symptoms, we performed a network analysis of Olink mediators highlighted by PLR within each LC group. COLEC12 and markers of endothelial and mucosal inflammation (MATN2, PCDH1, ROBO1, ISM1, ANGPTL2, TGF-α and TFF2) were highly correlated within the cardioresp, fatigue and anxiety/depression groups (Fig. 2 and Extended Data Fig. 7 ). Elevated PCDH1, an adhesion protein modulating airway inflammation 35 , was highly correlated with other inflammatory proteins associated with the cardioresp group (Fig. 2 ), suggesting that systemic inflammation may arise from the lung in these individuals. This was supported by increased expression of IL-3RA, which regulates innate immune responses in the lung through interactions with circulating IL-3 (ref. 36 ), in fatigue (Figs. 1d and 2 ), which correlated with markers of tissue inflammation, including PCDH1 (Fig. 2 ). MATN2 and ISM1, mucosal proteins that enhance inflammation 37 , 38 , were highly correlated in the GI group (Fig. 2 ), highlighting the role of tissue-specific inflammation in different LC groups. SCG3 correlated less closely with mediators in the GI group (Fig. 2 ), suggesting that the brain–gut axis may contribute separately to some GI symptoms. SPON-1, which regulates neural growth 21 , was the most highly correlated mediator in the cognitive group (Fig. 2 and Extended Data Fig. 7 ), highlighting that processes within nerve tissue may underlie this group. These observations suggested that inflammation might arise from mucosal tissues and that additional mechanisms may contribute to pathophysiology underlying the GI and cognitive groups.

Network analysis of Olink mediators associated with cardioresp ( n = 365), fatigue ( n = 314), anxiety/depression ( n = 202), GI ( n = 124) and cognitive groups ( n = 60). Each node corresponds to a protein mediator identified by PLR. The edges (blue lines) were weighted according to the size of Spearman’s rank correlation coefficient between proteins. All edges represent positive and significant correlations ( P < 0.05) after FDR adjustment.

Women were more likely to experience LC (Table 1 ), as found in previous studies 1 . As estrogen can influence immunological responses 39 , we investigated whether hormonal differences between men and women with LC in our cohort explained this trend. We grouped men and women with LC symptoms into two age groups (those younger than 50 years and those 50 years and older, using age as a proxy for menopause status in women) and compared mediator levels between men and women in each age group, prioritizing those identified by PLR to be higher in LC compared with recovered. As we aimed to understand whether women with LC had stronger inflammatory responses than men with LC, we did not assess differences in men and women in the recovered group. IL-1R2 and MATN2 were significantly higher in women ≥50 years than men ≥50 years in the cardioresp group (Fig. 3a , IL-1R2 and MATN2) and the fatigue group (Fig. 3b ). In the GI group, CSF3 was higher in women ≥50 years compared with men ≥50 years (Fig. 3c ), indicating that the inflammatory markers observed in women were not likely to be estrogen-dependent. Women have been reported to have stronger innate immune responses to infection and to be at greater risk of autoimmunity 39 , possibly explaining why some women in the ≥50 years group had higher inflammatory proteins than men the same group. Proteins associated with the anxiety/depression (IL-1R2 P = 0.11 and MATN2 P = 0.61, Extended Data Fig. 8a ) and cognitive groups (CTSO P = 0.64 and NFASC P = 0.41, Extended Data Fig. 8b ) were not different between men and women in either age group, consistent with the absent/weak association between sex and these outcomes identified by PLR (Fig. 1e,g ). Though our findings suggested that nonhormonal differences in inflammatory responses may explain why some women are more likely to have LC, they require confirmation in adequately powered studies.

a – c , Olink-measured plasma protein levels (NPX) of IL-1R2 and MATN2 ( a and b ) and CSF3 ( c ) between LC men and LC women divided by age (<50 or ≥50 years) in the cardiorespiratory group (<50 years n = 8 and ≥50 years n = 270) ( a ), fatigue group (<50 years n = 81 and ≥50 years n = 227) ( b ) and GI group (<50 years n = 34 and ≥50 years n = 82) ( c ). the median values were compared between men and women using two-sided Wilcoxon signed-rank test, * P < 0.05, ** P < 0.01, *** P < 0.001 and **** P < 0.0001. The box plot center line represents the median, the boundaries represent IQR and the whisker length represents 1.5× IQR.

To test whether local respiratory tract inflammation persisted after COVID-19, we compared nasosorption samples from 89 participants (recovered, n = 31; LC, n = 33; and healthy SARS-CoV-2 naive controls, n = 25, Supplementary Tables 4 and 5 ). Several inflammatory markers were elevated in the upper respiratory tract post COVID (including IL-1α, CXCL10, CXCL11, TNF, VEGF and TFF2) when compared with naive controls, but similar between recovered and LC (Fig. 4a ). In the cardioresp group ( n = 29), inflammatory mediators elevated in plasma (for example, IL-6, APO-2, TGF-α and TFF2) were not elevated in the upper respiratory tract (Extended Data Fig. 9a ) and there was no correlation between plasma and nasal mediator levels (Extended Data Fig. 9b ). This exploratory analysis suggested upper respiratory tract inflammation post COVID was not specifically associated with cardiorespiratory symptoms.

a , Nasal cytokines measured by immunoassay in post-COVID participants ( n = 64) compared with healthy SARS-CoV-2 naive controls ( n = 25), and between the the cardioresp group ( n = 29) and the recovered group ( n = 31). The red values indicate significantly increased cytokine levels after FDR adjustment ( P < 0.05) using two-tailed Wilcoxon signed-rank test. b , SARS-CoV-2 N antigen measured in sputum by electrochemiluminescence from recovered ( n = 17) and pooled LC ( n = 23) groups, compared with BALF from SARS-CoV-2 naive controls ( n = 9). The horizontal dashed line indicates the lower limit of detection of the assay. c , Plasma S- and N-specific IgG responses measured by electrochemiluminescence in the LC ( n = 35) and recovered ( n = 19) groups. The median values were compared using two-sided Wilcoxon signed-rank tests, NS P > 0.05, * P < 0.05, ** P < 0.01, *** P < 0.001 and **** P < 0.0001. The box plot center lines represent the median, the boundaries represent IQR and the whisker length represents 1.5× IQR.

To explore whether SARS-CoV-2 persistence might explain the inflammatory profiles observed in the cardioresp group, we measured SARS-CoV-2 nucleocapsid (N) antigen in sputum from 40 participants (recovered n = 17 and LC n = 23) collected approximately 6 months post hospitalization (Supplementary Table 6 ). All samples were compared with prepandemic bronchoalveolar lavage fluid ( n = 9, Supplementary Table 4 ). Only four samples (recovered n = 2 and LC n = 2) had N antigen above the assay’s lower limit of detection, and there was no difference in N antigen concentrations between LC and recovered (Fig. 4b , P = 0.78). These observations did not exclude viral persistence, which might require tissues samples for detection 40 , 41 . On the basis of the hypothesis that persistent viral antigen might prevent a decline in antibody levels over time, we examined the titers of SARS-CoV-2-specific antibodies in unvaccinated individuals (recovered n = 19 and LC n = 35). SARS-CoV-2 N-specific ( P = 0.023) and spike (S)-specific ( P = 0.0040) immunoglobulin G (IgG) levels were elevated in LC compared with recovered (Fig. 4c ).

Overall, we identified myeloid inflammation and complement activation in the cardioresp, fatigue, anxiety/depression, cognitive and GI groups 6 months after hospitalization (Extended Data Fig. 10 ). Our findings build on results of smaller studies 5 , 6 , 42 and are consistent with a genome-wide association study that identified an independent association between LC and FOXP4 , which modulates neutrophilic inflammation and immune cell function 43 , 44 . In addition, we identified tissue-specific inflammatory elements, indicating that myeloid disturbance in different tissues may result in distinct symptoms. Multiple mechanisms for LC have been suggested, including autoimmunity, thrombosis, vascular dysfunction, SARS-CoV-2 persistence and latent virus reactivation 1 . All these processes involve myeloid inflammation and complement activation 45 . Complement activation in LC has been suggested in a proteomic study in 97 mostly nonhospitalized COVID-19 cases 42 and a study of 48 LC patients, of which one-third experienced severe acute disease 46 . As components of the complement system are known to have a short half-life 47 , ongoing complement activation suggests active inflammation rather than past tissue damage from acute infection.

Despite the heterogeneity of LC and the likelihood of coexisting or multiple etiologies, our work suggests some common pathways that might be targeted therapeutically and supports the rationale for several drugs currently under trial. Our finding of increased sCD58 levels (associated with suppression of monocyte–lymphocyte interactions 26 ) in the recovered group, strengthens our conclusion that myeloid inflammation is central to the biology of LC and that trials of steroids, IL-1 antagonists, JAK inhibitors, naltrexone and colchicine are justified. Although anticoagulants such as apixaban might prevent thrombosis downstream of complement dysregulation, they can also increase the risk of serious bleeding when given after COVID-19 hospitalization 48 . Thus, clinical trials, already underway, need to carefully assess the risks and benefits of anticoagulants (Supplementary Table 2 ).

Our finding of elevated S- and N-specific IgG in LC could suggest viral persistence, as found in other studies 6 , 42 , 49 . Our network analysis indicated that inflammatory proteins in the cardioresp group interacted strongly with ISM1 and ROBO1, which are expressed during respiratory tract infection and regulate lung inflammation 50 , 51 . Although we were unable to find SARS-CoV-2 antigen in sputum from our LC cases, we did not test for viral persistence in GI tract and lung tissue 40 , 41 or in plasma 52 . Evidence of SARS-CoV-2 persistence would justify trials of antiviral drugs (singly or in combination) in LC. It is also possible that autoimmune processes could result in an innate inflammatory profile in LC. Autoreactive B cells have been identified in LC patients with higher SARS-CoV-2-specific antibody titers in a study of mostly mild acute COVID cases (59% WHO 2–3) 42 , a different population from our study of hospitalized cases.

Our observations of distinct protein profiles in GI and cognitive groups support previous reports on distinct associations between Epstein–Barr virus reactivation and neurological symptoms, or autoantibodies and GI symptoms relative to other forms of LC 49 , 53 . We did not assess autoantibody induction but found evidence of brain–gut axis disturbance (SCG3) in the GI group, which occurs in many autoimmune diseases 54 . We found signatures suggestive of neuroinflammation (C1QA) in the cognitive group, consistent with findings of brain abnormalities on magnetic resonance imaging after COVID-19 hospitalization 55 , as well as findings of microglial activation in mice after COVID-19 (ref. 56 ). Proinflammatory signatures dominated in the cardioresp, fatigue and anxiety/depression groups and were consistent with those seen in non-COVID depression, suggesting shared mechanisms 57 . The association between markers of myeloid inflammation, including IL-3RA, and symptoms was greatest for fatigue. Whilst membrane-bound IL-3RA facilitates IL-3 signaling upstream of myelopoesis 36 its soluble form (measured in plasma) can bind IL-3 and can act as a decoy receptor, preventing monocyte maturation and enhancing immunopathology 58 . Monocytes from individuals with post-COVID fatigue are reported to have abnormal expression profiles (including reduced CXCR2), suggestive of altered maturation and migration 5 , 59 . Lung-specific inflammation was suggested by the association between PCDH1 (an airway epithelial adhesion molecule 35 ) and cardioresp symptoms.

Our observations do not align with all published observations on LC. One proteomic study of 55 LC cases after generally mild (WHO 2–3) acute disease found that TNF and IFN signatures were elevated in LC 3 . Vasculoproliferative processes and metabolic disturbance have been reported in LC 4 , 60 , but these studies used uninfected healthy individuals for comparison and cannot distinguish between LC-specific phenomena and residual post-COVID inflammation. A study of 63 adults (LC, n = 50 and recovered, n = 13) reported no association between immune cell activation and LC 3 months after infection 61 , though myeloid inflammation was not directly measured, and 3 months post infection may be too early to detect subtle differences between LC and recovered cases due to residual acute inflammation.

Our study has limitations. We designed the study to identify inflammatory markers identifying pathways underlying LC subgroups rather than diagnostic biomarkers. The ORs we report are small, but associations were consistent across alternative methods of analysis and when using different LC definitions. Small effect sizes can be expected when using PLR, which shrinks correlated mediator coefficients to reflect combined effects and prevent colinear inflation 62 , and could also result from measurement of plasma mediators that may underestimate tissue inflammation. Although our LC cohort is large compared with most other published studies, some of our subgroups are small (only 60 cases were designated cognitive). Though the performance of the cognitive PLR model was adequate, our findings should be validated in larger studies. It should be noted that our cohort of hospitalized cases may not represent all types of LC, especially those occurring after mild infection. We looked for an effect of acute disease severity within our study and did not find it, and are reassured that the inflammatory profiles we observed were consistent with those seen in smaller studies including nonhospitalized cases 42 , 46 . Studies of posthospital LC may be confounded by ‘posthospital syndrome’, which encompasses general and nonspecific effects of hospitalization (particularly intensive care) 63 .

In conclusion, we found markers of myeloid inflammation and complement activation in our large prospective posthospital cohort of patients with LC, in addition to distinct inflammatory patterns in patients with cognitive impairment or gastrointestinal symptoms. These findings show the need to consider subphenotypes in managing patients with LC and support the use of antiviral or immunomodulatory agents in controlled therapeutic trials.

Study design and ethics

After hospitalization for COVID-19, adults who had no comorbidity resulting in a prognosis of less than 6 months were recruited to the PHOSP-COVID study ( n = 719). Patients hospitalized between February 2020 and January 2021 were recruited. Both sexes were recruited and gender was self-reported (female, n = 257 and male, n = 462). Written informed consent was obtained from all patients. Ethical approvals for the PHOSP-COVID study were given by Leeds West Research Ethics Committee (20/YH/0225).

Symptom data and samples were prospectively collected from individuals approximately 6 months (IQR 5.1–6.8 months and range 3.0–8.3 months) post hospitalization (Fig. 1a ), via the PHOSP-COVID multicenter United Kingdom study 64 . Data relating to patient demographics and acute admission were collected via the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization Clinical Characterisation Protocol United Kingdom (ISARIC4C study; IRAS260007/IRAS126600) (ref. 65 ). Adults hospitalized during the SARS-CoV-2 pandemic were systematically recruited into ISARIC4C. Written informed consent was obtained from all patients. Ethical approval was given by the South Central–Oxford C Research Ethics Committee in England (reference 13:/SC/0149), Scotland A Research Ethics Committee (20/SS/0028) and WHO Ethics Review Committee (RPC571 and RPC572l, 25 April 2013).

Data were collected to account for variables affecting symptom outcome, via hospital records and self-reporting. Acute disease severity was classified according to the WHO clinical progression score: WHO class 3–4: no oxygen therapy; class 5: oxygen therapy; class 6: noninvasive ventilation or high-flow nasal oxygen; and class 7–9: managed in critical care 9 . Clinical data were used to place patients into six categories: ‘recovered’, ‘GI’, ‘cardiorespiratory’, ‘fatigue’, ‘cognitive impairment’ and ‘anxiety/depression’ (Supplementary Table 7 ). Patient-reported symptoms and validated clinical scores were used when feasible, including Medical Research Council (MRC) breathlessness score, dyspnea-12 score, Functional Assessment of Chronic Illness Therapy (FACIT) score, Patient Health Questionnaire (PHQ)-9 and Generalized Anxiety Disorder (GAD)-7. Cognitive impairment was defined as a Montreal Cognitive Assessment score <26. GI symptoms were defined as answering ‘Yes’ to the presence of at least two of the listed symptoms. ‘Recovered’ was defined by self-reporting. Patients were placed in multiple groups if they experienced a combination of symptoms.

Matched nasal fluid and sputum samples were prospectively collected from a subgroup of convalescent patients approximately 6 months after hospitalization via the PHOSP-COVID study. Nasal and bronchoalveolar lavage fluid (BALF) collected from healthy volunteers before the COVID-19 pandemic were used as controls (Supplementary Table 4 ). Written consent was obtained for all individuals and ethical approvals were given by London–Harrow Research Ethics Committee (13/LO/1899) for the collection of nasal samples and the Health Research Authority London–Fulham Research Ethics Committee (IRAS project ID 154109; references 14/LO/1023, 10/H0711/94 and 11/LO/1826) for BALF samples.

Ethylenediaminetetraacetic acid plasma was collected from whole blood taken by venepuncture and frozen at −80 °C as previously described 7 , 66 . Nasal fluid was collected using a NasosorptionTM FX·I device (Hunt Developments), which uses a synthetic absorptive matrix to collect concentrated nasal fluid. Samples were eluted and stored as previously described 67 . Sputum samples were collected via passive expectoration and frozen at −80 °C without the addition of buffers. Sputum samples from convalescent individuals were compared with BALF from healthy SARS-CoV-2-naive controls, collected before the pandemic. BALF samples were used to act as a comparison for lower respiratory tract samples since passively expectorated sputum from healthy SARS-CoV-2-naive individuals was not available. BALF samples were obtained by instillation and recovery of up to 240 ml of normal saline via a fiberoptic bronchoscope. BALF was filtered through 100 µM strainers into sterile 50 ml Falcon tubes, then centrifuged for 10 min at 400 g at 4 °C. The resulting supernatant was transferred into sterile 50 ml Falcon tubes and frozen at −80 °C until use. The full methods for BALF collection and processing have been described previously 68 , 69 .

Immunoassays

To determine inflammatory signatures that associated with symptom outcomes, plasma samples were analyzed on an Olink Explore 384 Inflammation panel 70 . Supplementary Table 8 (Appendix 1 ) lists all the analytes measured. To ensure the validity of results, samples were run in a single batch with the use of negative controls, plate controls in triplicate and repeated measurement of patient samples between plates in duplicate. Samples were randomized between plates according to site and sample collection date. Randomization between plates was blind to LC/recovered outcome. Data were first normalized to an internal extension control that was included in each sample well. Plates were standardized by normalizing to interplate controls, run in triplicate on each plate. Each plate contained a minimum of four patient samples, which were duplicates on another plate; these duplicate pairs allowed any plate to be linked to any other through the duplicates. Data were then intensity normalized across all cohort samples. Finally, Olink results underwent quality control processing and samples or analytes that did not reach quality control standards were excluded. Final normalized relative protein quantities were reported as log 2 NPX values.

To further validate our findings, we performed conventional electrochemiluminescence (ECL) assays and enzyme-linked immunosorbent assay for Olink mediators that were associated with symptom outcome ( Supplementary Methods ). Contemporaneously collected plasma samples were available from 58 individuals. Like most omics platforms, Olink measures relative quantities, so perfect agreement with conventional assays that measure absolute concentrations is not expected.

Sputum samples were thawed before analysis and sputum plugs were extracted with the addition of 0.1% dithiothreitol creating a one in two sample dilution, as previously described 71 . SARS-CoV-2 S and N proteins were measured by ECL S-plex assay at a fixed dilution of one in two (Mesoscale Diagnostics), as per the manufacturers protocol 72 . Control BALF samples were thawed and measured on the same plate, neat. The S-plex assay is highly sensitive in detecting viral antigen in respiratory tract samples 73 .

Nasal cytokines were measured by ECL (mesoscale discovery) and Luminex bead multiplex assays (Biotechne). The full methods and list of analytes are detailed in Supplementary Methods .

Statistics and reproducibility

Clinical data was collected via the PHOSP REDCap database, to which access is available under reasonable request as per the data sharing statement in the manuscript. All analyses were performed within the Outbreak Data Analysis Platform (ODAP). All data and code can be accessed using information in the ‘Data sharing’ and ‘Code sharing’ statements at the end of the manuscript. No statistical method was used to predetermine sample size. Data distribution was assumed to be normal but this was not formally tested. Olink assays and immunoassays were randomized and investigators were blinded to outcomes.

To determine protein signatures that associated with each symptom outcome, a ridge PLR was used. PLR shrinks coefficients to account for combined effects within high-dimensional data, preventing false discovery while managing multicollinearity 34 . Thus, PLR was chosen a priori as the most appropriate model to assess associations between a large number of explanatory variables (that may work together to mediate effects) and symptom outcome 34 , 62 , 70 , 74 . In keeping with our aim to perform an unbiased exploration of inflammatory process, the model alpha was set to zero, facilitating regularization without complete penalization of any mediator. This enabled review of all possible mediators that might associate with LC 62 .

A 50 repeats tenfold nested cross-validation was used to select the optimal lambda for each model and assess its accuracy (Extended Data Fig. 1 ). The performance of the cognitive impairment model was influenced by the imbalance in size of the symptom group ( n = 60) relative to recovered ( n = 250). The model was weighted to account for this imbalance resulting in a sensitivity of 0.98, indicating its validity. We have expanded on the model performance and validation approaches in Supplementary Information .

Age, sex, acute disease severity and preexisting comorbidities were included as covariates in the PLR analysis (Supplementary Tables 1 and 3 ). Covariates were selected a priori using features reported to influence the risk of LC and inflammatory responses 1 , 39 , 64 , 75 . Ethnicity was not included since it has been shown not to predict symptom outcome in this cohort 64 . Individuals with missing data were excluded from the regression analysis. Each symptom group was compared with the ‘recovered’ group. The model coefficients of each covariate were converted into ORs for each outcome and visualized in a forest plot, after removing variables associated with regularized OR between 0.98 and 1.02 or in cases where most variables fell outside of this range, using mediators associated with the highest decile of coefficients either side of this range. This enabled exclusion of mediators with effect sizes that were unlikely to have clinical or mechanistic importance since the ridge PLR shrinks and orders coefficients according to their relative importance rather than making estimates with standard error. Thus, confidence intervals cannot be appropriately derived from PLR, and forest plot error bars were calculated using the median accuracy of the model generated by the nested cross-validation. To verify observations made through PLR analysis, we also performed an unadjusted PLR, an unadjusted logistic regression and a PLS analysis. Univariate analyses using Wilcoxon signed-rank test was also performed (Supplementary Table 8 , Appendix 1 ). Analyses were performed in R version 4.2.0 using ‘data.table v1.14.2’, ‘EnvStats v2.7.0’ ‘tidyverse v1.3.2’, ‘lme4 v1.1-32’, ‘caret v6.0-93’, ‘glmnet v4.1-6’, ‘mdatools v0.14.0’, ‘ggpubbr v0.4.0’ and ‘ggplot2 v3.3.6’ packages.

To further investigate the relationship between proteins elevated in each symptom group, we performed a correlation network analysis using Spearman’s rank correlation coefficient and false discovery rate (FDR) thresholding. The mediators visualized in the PLR forest plots, which were associated with cardiorespiratory symptoms, fatigue, anxiety/depression GI symptoms and cognitive impairment were used, respectively. Analyses were performed in R version 4.2.0 using ‘bootnet v1.5.6 ’ and ‘qgraph v1.9.8 ’ packages.

To determine whether differences in protein levels between men and women related to hormonal differences, we divided each symptom group into premenopausal and postmenopausal groups using an age cutoff of 50 years old. Differences between sexes in each group were determined using the Wilcoxon signed-rank test. To understand whether antigen persistence contributed to inflammation in adults with LC, the median viral antigen concentration from sputum/BALF samples and cytokine concentrations from nasal samples were compared using the Wilcoxon signed-rank test. All tests were two-tailed and statistical significance was defined as a P value < 0.05 after adjustment for FDR ( q -value of 0.05). Analyses were performed in R version 4.2.0 using ‘bootnet v1.5.6’ and ‘qgraph v1.9.8’ packages.

Extended Data Fig. 10 was made using Biorender, accessed at www.biorender.com .

Reporting summary

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

Data availability

This is an open access article under the CC BY 4.0 license.

The PHOSP-COVID protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online at ref. 76 . Access to these materials can be granted by contacting [email protected] and [email protected].

The ISARIC4C protocol, data sharing and publication policy are available at https://isaric4c.net . ISARIC4C’s Independent Data and Material Access Committee welcomes applications for access to data and materials ( https://isaric4c.net ).

The datasets used in the study contain extensive clinical information at an individual level that prevent them from being deposited in an public depository due to data protection policies of the study. Study data can only be accessed via the ODAP, a protected research environment. All data used in this study are available within ODAP and accessible under reasonable request. Data access criteria and information about how to request access is available online at ref. 76 . If criteria are met and a request is made, access can be gained by signing the eDRIS user agreement.

Code availability

Code was written within the ODAP, using R v4.2.0 and publicly available packages (‘data.table v1.14.2’, ‘EnvStats v2.7.0’, ‘tidyverse v1.3.2’, ‘lme4 v1.1-32’, ‘caret v6.0-93’, ‘glmnet v4.1-6’, ‘mdatools v0.14.0’, ‘ggpubbr v0.4.0’, ‘ggplot2 v3.3.6’, ‘bootnet v1.5.6’ and ‘qgraph v1.9.8’ packages). No new algorithms or functions were created and code used in-built functions in listed packages available on CRAN. The code used to generate data and to analyze data is publicly available at https://github.com/isaric4c/wiki/wiki/ISARIC ; https://github.com/SurgicalInformatics/cocin_cc and https://github.com/ClaudiaEfstath/PHOSP_Olink_NatImm .

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Acknowledgements

This research used data assets made available by ODAP as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref. MC_PC_20058). This work is supported by the following grants: the PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research (NIHR; grant references MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the MRC (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference C18616/A25153). Other grants that have supported this work include the UK Coronavirus Immunology Consortium (funder reference 1257927), the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit in Respiratory Infections at Imperial College London and NIHR Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, (NIHR award 200907), Wellcome Trust and Department for International Development (215091/Z/18/Z), Health Data Research UK (grant code 2021.0155), MRC (grant code MC_UU_12014/12) and NIHR Clinical Research Network for providing infrastructure support for this research. We also acknowledge the support of the MRC EMINENT Network (MR/R502121/1), which is cofunded by GSK, the Comprehensive Local Research Networks, the MRC HIC-Vac network (MR/R005982/1) and the RSV Consortium in Europe Horizon 2020 Framework Grant 116019. F.L. is supported by an MRC clinical training fellowship (award MR/W000970/1). C.E. is funded by NIHR (grant P91258-4). L.-P.H. is supported by Oxford NIHR Biomedical Research Centre. A.A.R.T. is supported by a British Heart Foundation (BHF) Intermediate Clinical Fellowship (FS/18/13/33281). S.L.R.-J. receives support from UK Research and Innovation (UKRI), Global Challenges Research Fund (GCRF), Rosetrees Trust, British HIV association (BHIVA), European & Developing Countries Clinical Trials Partnership (EDCTP) and Globvac. J.D.C. has grants from AstraZeneca, Boehringer Ingelheim, GSK, Gilead Sciences, Grifols, Novartis and Insmed. R.A.E. holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). A. Horsley is currently supported by UK Research and Innovation, NIHR and NIHR Manchester BRC. B.R. receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. D.G.W. is supported by an NIHR Advanced Fellowship. A. Ho has received support from MRC and for the Coronavirus Immunology Consortium (MR/V028448/1). L.T. is supported by the US Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085 and the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections (NIHR200907) at the University of Liverpool in partnership with UK Health Security Agency (UK-HSA), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. L.V.W. has received support from UKRI, GSK/Asthma and Lung UK and NIHR for this study. M.G.S. has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool. J.K.B. is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1 and MC_PC_20029). The funders were not involved in the study design, interpretation of data or writing of this manuscript. The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care (DHSC), the Department for International Development (DID), NIHR, MRC, the Wellcome Trust, UK-HSA, the National Health Service or the Department of Health. P.J.M.O. is supported by a NIHR Senior Investigator Award (award 201385). We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the PHOSP-COVID study at all of the 65 NHS trusts/health boards and 25 research institutions across the United Kingdom, as well as those who contributed to setting up and delivering the ISARIC4C study at 305 NHS trusts/health boards. We also thank all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland and Public Health England. We thank K. Holmes at the NIHR Office for Clinical Research Infrastructure for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well the NIHR Office for Clinical Research Infrastructure for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer’s Research UK, Asthma and Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and Long Covid Support. We also thank G. Khandaker and D. C. Newcomb who provided valuable feedback on this work. Extended Data Fig. 10 was created using Biorender.

Author information

These authors contributed equally: Felicity Liew, Claudia Efstathiou, Ryan S. Thwaites, Peter J. M. Openshaw.

Authors and Affiliations

National Heart and Lung Institute, Imperial College London, London, UK

Felicity Liew, Claudia Efstathiou, Sara Fontanella, Dawid Swieboda, Jasmin K. Sidhu, Stephanie Ascough, Onn Min Kon, Luke S. Howard, Jennifer K. Quint, Christopher Chiu, Ryan S. Thwaites, Peter J. M. Openshaw, Jake Dunning & Peter J. M. Openshaw

Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK

Matthew Richardson, Ruth Saunders, Olivia C. Leavy, Omer Elneima, Hamish J. C. McAuley, Amisha Singapuri, Marco Sereno, Victoria C. Harris, Neil J. Greening, Rachael A. Evans, Louise V. Wain, Christopher Brightling & Ananga Singapuri

NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

Shona C. Moore, Daniel G. Wootton, Malcolm G. Semple, Lance Turtle, William A. Paxton & Georgios Pollakis

The Imperial Clinical Respiratory Research Unit, Imperial College NHS Trust, London, UK

Noura Mohamed

Cardiovascular Research Team, Imperial College Healthcare NHS Trust, London, UK

Jose Nunag & Clara King

Department of Population Health Sciences, University of Leicester, Leicester, UK

Olivia C. Leavy, Louise V. Wain & Beatriz Guillen-Guio

NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK

Aarti Shikotra

Centre for Exercise and Rehabilitation Science, NIHR Leicester Biomedical Research Centre-Respiratory, University of Leicester, Leicester, UK

Linzy Houchen-Wolloff

Usher Institute, University of Edinburgh, Edinburgh, UK

Nazir I. Lone, Luke Daines, Annemarie B. Docherty, Nazir I. Lone, Matthew Thorpe, Annemarie B. Docherty, Thomas M. Drake, Cameron J. Fairfield, Ewen M. Harrison, Stephen R. Knight, Kenneth A. Mclean, Derek Murphy, Lisa Norman, Riinu Pius & Catherine A. Shaw

Centre for Medical Informatics, The Usher Institute, University of Edinburgh, Edinburgh, UK

Matthew Thorpe, Annemarie B. Docherty, Ewen M. Harrison, J. Kenneth Baillie, Sarah L. Rowland-Jones, A. A. Roger Thompson & Thushan de Silva

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

A. A. Roger Thompson, Sarah L. Rowland-Jones, Thushan I. de Silva & James D. Chalmers

University of Dundee, Ninewells Hospital and Medical School, Dundee, UK

James D. Chalmers & Ling-Pei Ho

MRC Human Immunology Unit, University of Oxford, Oxford, UK

Ling-Pei Ho & Alexander Horsley

Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Alexander Horsley & Betty Raman

Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Betty Raman & Krisnah Poinasamy

Asthma + Lung UK, London, UK

Krisnah Poinasamy & Michael Marks

Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK

Michael Marks

Hospital for Tropical Diseases, University College London Hospital, London, UK

Division of Infection and Immunity, University College London, London, UK

Michael Marks & Mahdad Noursadeghi

MRC Centre for Virus Research, School of Infection and Immunity, University of Glasgow, Glasgow, UK

Antonia Ho & William Greenhalf

Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

William Greenhalf & J. Kenneth Baillie

The Roslin Institute, University of Edinburgh, Edinburgh, UK

J. Kenneth Baillie, J. Kenneth Baillie, Sara Clohisey, Fiona Griffiths, Ross Hendry, Andrew Law & Wilna Oosthuyzen

Pandemic Science Hub, University of Edinburgh, Edinburgh, UK

J. Kenneth Baillie

The Pandemic Institute, University of Liverpool, Liverpool, UK

Malcolm G. Semple & Lance Turtle

University of Manchester, Manchester, UK

Kathryn Abel, Perdita Barran, H. Chinoy, Bill Deakin, M. Harvie, C. A. Miller, Stefan Stanel & Drupad Trivedi

Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK

Kathryn Abel & J. Kenneth Baillie

North Bristol NHS Trust and University of Bristol, Bristol, UK

H. Adamali, David Arnold, Shaney Barratt, A. Dipper, Sarah Dunn, Nick Maskell, Anna Morley, Leigh Morrison, Louise Stadon, Samuel Waterson & H. Welch

University of Edinburgh, Manchester, UK

Davies Adeloye, D. E. Newby, Riinu Pius, Igor Rudan, Manu Shankar-Hari, Catherine Sudlow, Sarah Walmsley & Bang Zheng

King’s College Hospital NHS Foundation Trust and King’s College London, London, UK

Oluwaseun Adeyemi, Rita Adrego, Hosanna Assefa-Kebede, Jonathon Breeze, S. Byrne, Pearl Dulawan, Amy Hoare, Caroline Jolley, Abigail Knighton, M. Malim, Sheetal Patale, Ida Peralta, Natassia Powell, Albert Ramos, K. Shevket, Fabio Speranza & Amelie Te

Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Laura Aguilar Jimenez, Gill Arbane, Sarah Betts, Karen Bisnauthsing, A. Dewar, Nicholas Hart, G. Kaltsakas, Helen Kerslake, Murphy Magtoto, Philip Marino, L. M. Martinez, Marlies Ostermann, Jennifer Rossdale & Teresa Solano

Royal Free London NHS Foundation Trust, London, UK

Shanaz Ahmad, Simon Brill, John Hurst, Hannah Jarvis, C. Laing, Lai Lim, S. Mandal, Darwin Matila, Olaoluwa Olaosebikan & Claire Singh

University Hospital Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK

N. Ahmad Haider, Catherine Atkin, Rhiannon Baggott, Michelle Bates, A. Botkai, Anna Casey, B. Cooper, Joanne Dasgin, Camilla Dawson, Katharine Draxlbauer, N. Gautam, J. Hazeldine, T. Hiwot, Sophie Holden, Karen Isaacs, T. Jackson, Vicky Kamwa, D. Lewis, Janet Lord, S. Madathil, C. McGee, K. Mcgee, Aoife Neal, Alex Newton-Cox, Joseph Nyaboko, Dhruv Parekh, Z. Peterkin, H. Qureshi, Liz Ratcliffe, Elizabeth Sapey, J. Short, Tracy Soulsby, J. Stockley, Zehra Suleiman, Tamika Thompson, Maximina Ventura, Sinead Walder, Carly Welch, Daisy Wilson, S. Yasmin & Kay Por Yip

Stroke Association, London, UK

Rubina Ahmed & Richard Francis

University College London Hospital and University College London, London, UK

Nyarko Ahwireng, Dongchun Bang, Donna Basire, Jeremy Brown, Rachel Chambers, A. Checkley, R. Evans, M. Heightman, T. Hillman, Joseph Jacob, Roman Jastrub, M. Lipman, S. Logan, D. Lomas, Marta Merida Morillas, Hannah Plant, Joanna Porter, K. Roy & E. Wall

Oxford University Hospitals NHS Foundation Trust and University of Oxford, Oxford, UK

Mark Ainsworth, Asma Alamoudi, Angela Bloss, Penny Carter, M. Cassar, Jin Chen, Florence Conneh, T. Dong, Ranuromanana Evans, V. Ferreira, Emily Fraser, John Geddes, F. Gleeson, Paul Harrison, May Havinden-Williams, P. Jezzard, Ivan Koychev, Prathiba Kurupati, H. McShane, Clare Megson, Stefan Neubauer, Debby Nicoll, C. Nikolaidou, G. Ogg, Edmund Pacpaco, M. Pavlides, Yanchun Peng, Nayia Petousi, John Pimm, Najib Rahman, M. J. Rowland, Kathryn Saunders, Michael Sharpe, Nick Talbot, E. M. Tunnicliffe & C. Xie

St George’s University Hospitals NHS Foundation Trust, London, UK

Mariam Ali, Raminder Aul, A. Dunleavy, D. Forton, Mark Mencias, N. Msimanga, T. Samakomva, Sulman Siddique, Vera Tavoukjian & J. Teixeira

University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK

M. Aljaroof, Natalie Armstrong, H. Arnold, Hnin Aung, Majda Bakali, M. Bakau, E. Baldry, Molly Baldwin, Charlotte Bourne, Michelle Bourne, Nigel Brunskill, P. Cairns, Liesel Carr, Amanda Charalambou, C. Christie, Melanie Davies, Enya Daynes, Sarah Diver, Rachael Dowling, Sarah Edwards, C. Edwardson, H. Evans, J. Finch, Sarah Glover, Nicola Goodman, Bibek Gooptu, Kate Hadley, Pranab Haldar, Beverley Hargadon, W. Ibrahim, L. Ingram, Kamlesh Khunti, A. Lea, D. Lee, Gerry McCann, P. McCourt, Teresa Mcnally, George Mills, Will Monteiro, Manish Pareek, S. Parker, Anne Prickett, I. N. Qureshi, A. Rowland, Richard Russell, Salman Siddiqui, Sally Singh, J. Skeemer, M. Soares, E. Stringer, T. Thornton, Martin Tobin, T. J. C. Ward, F. Woodhead, Tom Yates & A. J. Yousuf

University of Exeter, Exeter, UK

Louise Allan, Clive Ballard & Andrew McGovern

University of Leicester, Leicester, UK

Richard Allen, Michelle Bingham, Terry Brugha, Selina Finney, Rob Free, Don Jones, Claire Lawson, Daniel Lozano-Rojas, Gardiner Lucy, Alistair Moss, Elizabeta Mukaetova-Ladinska, Petr Novotny, Kimon Ntotsis, Charlotte Overton, John Pearl, Tatiana Plekhanova, M. Richardson, Nilesh Samani, Jack Sargant, Ruth Saunders, M. Sharma, Mike Steiner, Chris Taylor, Sarah Terry, C. Tong, E. Turner, J. Wormleighton & Bang Zhao

Liverpool University Hospitals NHS Foundation Trust and University of Liverpool, Liverpool, UK

Lisa Allerton, Ann Marie Allt, M. Beadsworth, Anthony Berridge, Jo Brown, Shirley Cooper, Andy Cross, Sylviane Defres, S. L. Dobson, Joanne Earley, N. French, Kera Hainey, Hayley Hardwick, Jenny Hawkes, Victoria Highett, Sabina Kaprowska, Angela Key, Lara Lavelle-Langham, N. Lewis-Burke, Gladys Madzamba, Flora Malein, Sophie Marsh, Chloe Mears, Lucy Melling, Matthew Noonan, L. Poll, James Pratt, Emma Richardson, Anna Rowe, Victoria Shaw, K. A. Tripp, Lilian Wajero, S. A. Williams-Howard, Dan Wootton & J. Wyles

Sherwood Forest Hospitals NHS Foundation Trust, Nottingham, UK

Lynne Allsop, Kaytie Bennett, Phil Buckley, Margaret Flynn, Mandy Gill, Camelia Goodwin, M. Greatorex, Heidi Gregory, Cheryl Heeley, Leah Holloway, Megan Holmes, John Hutchinson, Jill Kirk, Wayne Lovegrove, Terri Ann Sewell, Sarah Shelton, D. Sissons, Katie Slack, Susan Smith, D. Sowter, Sarah Turner, V. Whitworth & Inez Wynter

Nottingham University Hospitals NHS Trust and University of Nottingham, London, UK

Paula Almeida, Akram Hosseini, Robert Needham & Karen Shaw

Manchester University NHS Foundation Trust and University of Manchester, London, UK

Bashar Al-Sheklly, Cristina Avram, John Blaikely, M. Buch, N. Choudhury, David Faluyi, T. Felton, T. Gorsuch, Neil Hanley, Tracy Hussell, Zunaira Kausar, Natasha Odell, Rebecca Osbourne, Karen Piper Hanley, K. Radhakrishnan & Sue Stockdale

Imperial College London, London, UK

Danny Altmann, Anew Frankel, Luke S. Howard, Desmond Johnston, Liz Lightstone, Anne Lingford-Hughes, William Man, Steve McAdoo, Jane Mitchell, Philip Molyneaux, Christos Nicolaou, D. P. O’Regan, L. Price, Jennifer K. Quint, David Smith, Jonathon Valabhji, Simon Walsh, Martin Wilkins & Michelle Willicombe

Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK

Maria Alvarez Corral, Ava Maria Arias, Emily Bevan, Denise Griffin, Jane Martin, J. Owen, Sheila Payne, A. Prabhu, Annabel Reed, Will Storrar, Nick Williams & Caroline Wrey Brown

British Heart Foundation, Birmingham, UK

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NHS Greater Glasgow and Clyde Health Board and University of Glasgow, Glasgow, UK

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University of Oxford, Oxford, UK

Charalambos Antoniades, A. Bates, M. Beggs, Kamaldeep Bhui, Katie Breeze, K. M. Channon, David Clark, X. Fu, Masud Husain, Lucy Kingham, Paul Klenerman, Hanan Lamlum, X. Li, E. Lukaschuk, Celeste McCracken, K. McGlynn, R. Menke, K. Motohashi, T. E. Nichols, Godwin Ogbole, S. Piechnik, I. Propescu, J. Propescu, A. A. Samat, Z. B. Sanders, Louise Sigfrid & M. Webster

Belfast Health and Social Care Trust and Queen’s University Belfast, Belfast, UK

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A. Ashish, Josh Cooper & Emma Robinson

Leeds Teaching Hospitals and University of Leeds, Leeds, UK

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East Cheshire NHS Trust, Macclesfield, UK

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University of Nottingham, Nottingham, UK

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MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK

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University of Southampton, London, UK

David Baldwin, P. C. Calder, Nathan Huneke & Gemma Simons

Royal Brompton and Harefield Clinical Group, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

R. E. Barker, Daniele Cristiano, N. Dormand, P. George, Mahitha Gummadi, S. Kon, Kamal Liyanage, C. M. Nolan, B. Patel, Suhani Patel, Oliver Polgar, L. Price, P. Shah, Suver Singh & J. A. Walsh

York and Scarborough NHS Foundation Trust, York, UK

Laura Barman, Claire Brookes, K. Elliott, L. Griffiths, Zoe Guy, Kate Howard, Diana Ionita, Heidi Redfearn, Carol Sarginson & Alison Turnbull

NHS Highland, Inverness, UK

Fiona Barrett, A. Donaldson & Beth Sage

Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK

Helen Baxendale, Lucie Garner, C. Johnson, J. Mackie, Alice Michael, J. Newman, Jamie Pack, K. Paques, H. Parfrey, J. Parmar & A. Reddy

University Hospitals of Derby and Burton, Derby, UK

Paul Beckett, Caroline Dickens & Uttam Nanda

NHS Lanarkshire, Hamilton, UK

Murdina Bell, Angela Brown, M. Brown, R. Hamil, Karen Leitch, L. Macliver, Manish Patel, Jackie Quigley, Andrew Smith & B. Welsh

Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Clinical Research Facility and University of Cambridge, Cambridge, UK

Areti Bermperi, Isabel Cruz, K. Dempsey, Anne Elmer, Jonathon Fuld, H. Jones, Sherly Jose, Stefan Marciniak, M. Parkes, Carla Ribeiro, Jessica Taylor, Mark Toshner, L. Watson & J. Worsley

Loughborough University, Loughborough, UK

Lettie Bishop & David Stensel

Betsi Cadwallader University Health Board, Bangor, UK

Annette Bolger, Ffyon Davies, Ahmed Haggar, Joanne Lewis, Arwel Lloyd, R. Manley, Emma McIvor, Daniel Menzies, K. Roberts, W. Saxon, David Southern, Christian Subbe & Victoria Whitehead

Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK

Charlotte Bolton, J. Bonnington, Melanie Chrystal, Catherine Dupont, Paul Greenhaff, Ayushman Gupta, W. Jang, S. Linford, Laura Matthews, Athanasios Nikolaidis, Sabrina Prosper & Andrew Thomas

King’s College London, London, UK

Kate Bramham, M. Brown, Khalida Ismail, Tim Nicholson, Carmen Pariante, Claire Sharpe, Simon Wessely & J. Whitney

Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK

Lucy Brear, Karen Regan, Dinesh Saralaya & Kim Storton

South London and Maudsley NHS Foundation Trust and King’s College London, London, UK

G. Breen & M. Hotopf

London School of Hygiene and Tropical Medicine, London, UK

Andrew Briggs

Whittington Health NHS Trust, London, UK

E. Bright, P. Crisp, Ruvini Dharmagunawardena & M. Stern

Cardiff and Vale University Health Board, Cardiff, UK

Lauren Broad, Teriann Evans, Matthew Haynes, L. Jones, Lucy Knibbs, Alison McQueen, Catherine Oliver, Kerry Paradowski, Ramsey Sabit & Jenny Williams

Yeovil District Hospital NHS Foundation Trust, Yeovil, UK

Andrew Broadley

University of Birmingham, Birmingham, UK

Mattew Broome, Paul McArdle, Paul Moss, David Thickett, Rachel Upthegrove, Dan Wilkinson, David Wraith & Erin L. Aldera

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

Anda Bularga

University of Cambridge, Cambridge, UK

Ed Bullmore, Jonathon Heeney, Claudia Langenberg, William Schwaeble, Charlotte Summers & J. Weir McCall

NIHR Leicester Biomedical Research Centre–Respiratory Patient and Public Involvement Group, Leicester, UK

Jenny Bunker, Rhyan Gill & Rashmita Nathu

Imperial College Healthcare NHS Trust and Imperial College London, London, UK

L. Burden, Ellen Calvelo, Bethany Card, Caitlin Carr, Edwin Chilvers, Donna Copeland, P. Cullinan, Patrick Daly, Lynsey Evison, Tamanah Fayzan, Hussain Gordon, Sulaimaan Haq, Gisli Jenkins, Clara King, Onn Min Kon, Katherine March, Myril Mariveles, Laura McLeavey, Silvia Moriera, Unber Munawar, Uchechi Nwanguma, Lorna Orriss-Dib, Alexandra Ross, Maura Roy, Emily Russell, Katherine Samuel, J. Schronce, Neil Simpson, Lawrence Tarusan, David Thomas, Chloe Wood & Najira Yasmin

Harrogate and District NHD Foundation Trust, Harrogate, UK

Tracy Burdett, James Featherstone, Cathy Lawson, Alison Layton, Clare Mills & Lorraine Stephenson

Newcastle University/Chair of NIHR Dementia TRC, Newcastle, UK

Oxford University Hospitals NHS Foundation Trust, Oxford, UK

A. Burns & N. Kanellakis

Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK

Al-Tahoor Butt, Martina Coulding, Heather Jones, Susan Kilroy, Jacqueline McCormick, Jerome McIntosh, Heather Savill, Victoria Turner & Joanne Vere

University of Oxford, Nuffield Department of Medicine, Oxford, UK

University of Glasgow, Glasgow, UK

Jonathon Cavanagh, S. MacDonald, Kate O’Donnell, John Petrie, Naveed Sattar & Mark Spears

United Lincolnshire Hospitals NHS Trust, Grantham, UK

Manish Chablani & Lynn Osborne

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

Trudie Chalder

University Hospital of South Manchester NHS Foundation Trust, Manchester, UK

N. Chaudhuri

University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK

Caroline Childs, R. Djukanovic, S. Fletcher, Matt Harvey, Mark Jones, Elizabeth Marouzet, B. Marshall, Reena Samuel, T. Sass, Tim Wallis & Helen Wheeler

King’s College Hospital/Guy’s and St Thomas’ NHS FT, London, UK

A. Chiribiri & C. O’Brien

Barts Health NHS Trust, London, UK

K. Chong-James, C. David, W. Y. James, Paul Pfeffer & O. Zongo

NHS Lothian and University of Edinburgh, Edinburgh, UK

Gaunab Choudhury, S. Clohisey, Andrew Deans, J. Furniss, Ewen Harrison, S. Kelly & Aziz Sheikh

School of Cardiovascular Medicine and Sciences. King’s College London, London, UK

Phillip Chowienczyk

Lewisham and Greenwich NHS Trust, London, UK

Hywel Dda University Health Board, Haverfordwest, UK

S. Coetzee, Kim Davies, Rachel Ann Hughes, Ronda Loosley, Heather McGuinness, Abdelrahman Mohamed, Linda O’Brien, Zohra Omar, Emma Perkins, Janet Phipps, Gavin Ross, Abigail Taylor, Helen Tench & Rebecca Wolf-Roberts

NHS Tayside and University of Dundee, Dundee, UK

David Connell, C. Deas, Anne Elliott, J. George, S. Mohammed, J. Rowland, A. R. Solstice, Debbie Sutherland & Caroline Tee

Swansea Bay University Health Board, Port Talbot, UK

Lynda Connor, Amanda Cook, Gwyneth Davies, Tabitha Rees, Favas Thaivalappil & Caradog Thomas

Faculty of Medicine, Nursing and Health Sciences, School of Biomedical Sciences, Monash University, Melbourne, Victoria, Australia

Eamon Coughlan

Rotherham NHS Foundation Trust, Rotherham, UK

Alison Daniels, Anil Hormis, Julie Ingham & Lisa Zeidan

Salford Royal NHS Foundation Trust, Salford, UK

P. Dark, Nawar Diar-Bakerly, D. Evans, E. Hardy, Alice Harvey, D. Holgate, Sean Knight, N. Mairs, N. Majeed, L. McMorrow, J. Oxton, Jessica Pendlebury, C. Summersgill, R. Ugwuoke & S. Whittaker

Cwm Taf Morgannwg University Health Board, Mountain Ash, UK

Ellie Davies, Cerys Evenden, Alyson Hancock, Kia Hancock, Ceri Lynch, Meryl Rees, Lisa Roche, Natalie Stroud & T. Thomas-Woods

Borders General Hospital, NHS Borders, Melrose, UK

Joy Dawson, Hosni El-Taweel & Leanne Robinson

Aneurin Bevan University Health Board, Caerleon, UK

Amanda Dell, Sara Fairbairn, Nancy Hawkings, Jill Haworth, Michaela Hoare, Victoria Lewis, Alice Lucey, Georgia Mallison, Heeah Nassa, Chris Pennington, Andrea Price, Claire Price, Andrew Storrie, Gemma Willis & Susan Young

University of Exeter Medical School, Exeter, UK

London North West University Healthcare NHS Trust, London, UK

Shalin Diwanji, Sambasivarao Gurram, Padmasayee Papineni, Sheena Quaid, Gerlynn Tiongson & Ekaterina Watson

Alzheimer’s Research UK, Cambridge, UK

Hannah Dobson

Health and Care Research Wales, Cardiff, UK

Yvette Ellis

University of Bristol, Bristol, UK

Jonathon Evans

University of Sheffield, Sheffield, UK

L. Finnigan, Laura Saunders & James Wild

Great Western Hospital Foundation Trust, Swindon, UK

Eva Fraile & Jacinta Ugoji

Royal Devon and Exeter NHS Trust, Barnstaple, UK

Michael Gibbons

Kettering General Hospital NHS Trust, Kettering, UK

Anne-Marie Guerdette, Melanie Hewitt, R. Reddy, Katie Warwick & Sonia White

NIHR Leicester Biomedical Research Centre, Leicester, UK

Beatriz Guillen-Guio

University of Leeds, Leeds, UK

Elspeth Guthrie & Max Henderson

Royal Surrey NHS Foundation Trust, Cranleigh, UK

Mark Halling-Brown & Katherine McCullough

Chesterfield Royal Hospital NHS Trust, Calow, UK

Edward Harris & Claire Sampson

Long Covid Support, London, UK

Claire Hastie, Natalie Rogers & Nikki Smith

King’s College Hospital, NHS Foundation Trust and King’s College London, London, UK

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK

Simon Heller

NIHR Office for Clinical Research Infrastructure, London, UK

Katie Holmes

Asthma UK and British Lung Foundation Partnership, London, UK

Ian Jarrold & Samantha Walker

North Middlesex University Hospital NHS Trust, London, UK

Bhagy Jayaraman & Tessa Light

Action for Pulmonary Fibrosis, Peterborough, UK

Cardiff University, National Centre for Mental Health, Cardiff, UK

McPin Foundation, London, UK

Thomas Kabir

Roslin Institute, The University of Edinburgh, Edinburgh, UK

Steven Kerr

The Hillingdon Hospitals NHS Foundation Trust, London, UK

Samantha Kon, G. Landers, Harpreet Lota, Mariam Nasseri & Sofiya Portukhay

Queen Mary University of London, London, UK

Ania Korszun

Swansea University, Swansea Welsh Network, Hywel Dda University Health Board, Swansea, UK

Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK

Nazir I. Lone

Barts Heart Centre, London, UK

Barts Health NHS Trust and Queen Mary University of London, London, UK

Adrian Martineau

Salisbury NHS Foundation Trust, Salisbury, UK

Wadzanai Matimba-Mupaya & Sophia Strong-Sheldrake

University of Newcastle, Newcastle, UK

Hamish McAllister-Williams, Stella-Maria Paddick, Anthony Rostron & John Paul Taylor

Gateshead NHS Trust, Gateshead, UK

W. McCormick, Lorraine Pearce, S. Pugmire, Wendy Stoker & Ann Wilson

Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester, UK

Katherine McIvor

Kidney Research UK, Peterborough, UK

Aisling McMahon

NHS Dumfries and Galloway, Dumfries, UK

Michael McMahon & Paula Neill

Swansea University, Swansea, UK

MQ Mental Health Research, London, UK

Lea Milligan

BHF Centre for Cardiovascular Science, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

Nicholas Mills

Shropshire Community Health NHS Trust, Shropshire, UK

Sharon Painter, Johanne Tomlinson & Louise Warburton

Somerset NHS Foundation Trust, Taunton, UK

Sue Palmer, Dawn Redwood, Jo Tilley, Carinna Vickers & Tania Wainwright

Francis Crick Institute, London, UK

Markus Ralser

Manchester University NHD Foundation Trust, Manchester, UK

Pilar Rivera-Ortega

Diabetes UK, University of Glasgow, Glasgow, UK

Elizabeth Robertson

Barnsley Hospital NHS Foundation Trust, Barnsley, UK

Amy Sanderson

MRC–University of Glasgow Centre for Virus Research, Glasgow, UK

Janet Scott

Diabetes UK, London, UK

Kamini Shah

British Heart Foundation Centre, King’s College London, London, UK

King’s College Hospital NHS Foundation Trust, London, UK

University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK

Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

University College London NHS Foundation Trust, London and Barts Health NHS Trust, London, UK

Northumbria University, Newcastle upon Tyne, UK

Ioannis Vogiatzis

Swansea University and Swansea Welsh Network, Swansea, UK

N. Williams

DUK | NHS Digital, Salford Royal Foundation Trust, Salford, UK

Queen Alexandra Hospital, Portsmouth, UK

Kayode Adeniji

Princess Royal Hospital, Haywards Heath, UK

Daniel Agranoff & Chi Eziefula

Bassetlaw Hospital, Bassetlaw, UK

Darent Valley Hospital, Dartford, UK

Queen Elizabeth the Queen Mother Hospital, Margate, UK

Ana Alegria

School of Informatics, University of Edinburgh, Edinburgh, UK

Beatrice Alex, Benjamin Bach & James Scott-Brown

North East and North Cumbria Ingerated, Newcastle upon Tyne, UK

Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Petros Andrikopoulos, Kanta Chechi, Marc-Emmanuel Dumas, Julian Griffin, Sonia Liggi & Zoltan Takats

Section of Genomic and Environmental Medicine, Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UK

Petros Andrikopoulos, Marc-Emmanuel Dumas, Michael Olanipekun & Anthonia Osagie

John Radcliffe Hospital, Oxford, UK

Brian Angus

Royal Albert Edward Infirmary, Wigan, UK

Abdul Ashish

Manchester Royal Infirmary, Manchester, UK

Dougal Atkinson

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK

Section of Molecular Virology, Imperial College London, London, UK

Wendy S. Barclay

Furness General Hospital, Barrow-in-Furness, UK

Shahedal Bari

Hull University Teaching Hospital Trust, Kingston upon Hull, UK

Gavin Barlow

Hillingdon Hospital, Hillingdon, UK

Stella Barnass

St Thomas’ Hospital, London, UK

Nicholas Barrett

Coventry and Warwickshire, Coventry, UK

Christopher Bassford

St Michael’s Hospital, Bristol, UK

Sneha Basude

Stepping Hill Hospital, Stockport, UK

David Baxter

Royal Liverpool University Hospital, Liverpool, UK

Michael Beadsworth

Bristol Royal Hospital Children’s, Bristol, UK

Jolanta Bernatoniene

Scarborough Hospital, Scarborough, UK

John Berridge

Golden Jubilee National Hospital, Clydebank, UK

Colin Berry

Liverpool Heart and Chest Hospital, Liverpool, UK

Nicola Best

Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

Debby Bogaert & Clark D. Russell

James Paget University Hospital, Great Yarmouth, UK

Pieter Bothma & Darell Tupper-Carey

Aberdeen Royal Infirmary, Aberdeen, UK

Robin Brittain-Long

Adamson Hospital, Cupar, UK

Naomi Bulteel

Royal Devon and Exeter Hospital, Exeter, UK

Worcestershire Royal Hospital, Worcester, UK

Andrew Burtenshaw

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Gail Carson, Laura Merson & Louise Sigfrid

Conquest Hospital, Hastings, UK

Vikki Caruth

The James Cook University Hospital, Middlesbrough, UK

David Chadwick

Dorset County Hospital, Dorchester, UK

Duncan Chambler

Antimicrobial Resistance and Hospital Acquired Infection Department, Public Health England, London, UK

Meera Chand

Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK

Kanta Chechi

Royal Bournemouth General Hospital, Bournemouth, UK

Harrogate Hospital, Harrogate, UK

Jenny Child

Royal Blackburn Teaching Hospital, Blackburn, UK

Srikanth Chukkambotla

Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, UK

Richard Clark, Audrey Coutts, Lorna Donelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy & Nicola Wrobel

Torbay Hospital, Torquay, UK

Northern General Hospital, Sheffield, UK

Paul Collini, Cariad Evans & Gary Mills

Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK

Marie Connor, Jo Dalton, Chloe Donohue, Carrol Gamble, Michelle Girvan, Sophie Halpin, Janet Harrison, Clare Jackson, Laura Marsh, Stephanie Roberts & Egle Saviciute

Department of Infectious Disease, Imperial College London, London, UK

Graham S. Cooke & Shiranee Sriskandan

St Georges Hospital (Tooting), London, UK

Catherine Cosgrove

Blackpool Victoria Hospital, Blackpool, UK

Jason Cupitt & Joanne Howard

The Royal London Hospital, London, UK

Maria-Teresa Cutino-Moguel

MRC-University of Glasgow Centre for Virus Research, Glasgow, UK

Ana da Silva Filipe, Antonia Y. W. Ho, Sarah E. McDonald, Massimo Palmarini, David L. Robertson, Janet T. Scott & Emma C. Thomson

Salford Royal Hospital, Salford, UK

University Hospital of North Durham, Durham, UK

Chris Dawson

Norfolk and Norwich University Hospital, Norwich, UK

Samir Dervisevic

Intensive Care Unit, Royal Infirmary Edinburgh, Edinburgh, UK

Annemarie B. Docherty & Seán Keating

Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK

Cara Donegan & Rebecca G. Spencer

Salisbury District Hospital, Salisbury, UK

Phil Donnison

National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Gonçalo dos Santos Correia, Matthew Lewis, Lynn Maslen, Caroline Sands, Zoltan Takats & Panteleimon Takis

Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Gonçalo dos Santos Correia, Matthew Lewis, Lynn Maslen, Caroline Sands & Panteleimon Takis

Guy’s and St Thomas’, NHS Foundation Trust, London, UK

Sam Douthwaite, Michael MacMahon, Marlies Ostermann & Manu Shankar-Hari

The Royal Oldham Hospital, Oldham, UK

Andrew Drummond

European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille University Hospital, University of Lille, Lille, France

Marc-Emmanuel Dumas

McGill University and Genome Quebec Innovation Centre, Montreal, Qeubec, Canada

National Infection Service, Public Health England, London, UK

Jake Dunning & Maria Zambon

Hereford Count Hospital, Hereford, UK

Ingrid DuRand

Southampton General Hospital, Southampton, UK

Ahilanadan Dushianthan

Northampton General Hospital, Northampton, UK

Tristan Dyer

University Hospital of Wales, Cardiff, UK

Chrisopher Fegan

University Hospitals Bristol NHS Foundation Trust, Bristol, UK

Liverpool School of Tropical Medicine, Liverpool, UK

Tom Fletcher

Leighton Hospital, Crewe, UK

Duncan Fullerton & Elijah Matovu

Manor Hospital, Walsall, UK

Scunthorpe Hospital, Scunthorpe, UK

Sanjeev Garg

Cambridge University Hospital, Cambridge, UK

Effrossyni Gkrania-Klotsas

West Suffolk NHS Foundation Trust, Bury St Edmunds, UK

Basingstoke and North Hampshire Hospital, Basingstoke, UK

Arthur Goldsmith

North Cumberland Infirmary, Carlisle, UK

Clive Graham

Paediatric Liver, GI and Nutrition Centre and MowatLabs, King’s College Hospital, London, UK

Tassos Grammatikopoulos

Institute of Liver Studies, King’s College London, London, UK

Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK

Christopher A. Green

Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK

William Greenhalf

Institute for Global Health, University College London, London, UK

Rishi K. Gupta

NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK

Hayley Hardwick, Malcolm G. Semple, Tom Solomon & Lance C. W. Turtle

Warwick Hospital, Warwick, UK

Elaine Hardy

Birmingham Children’s Hospital, Birmingham, UK

Stuart Hartshorn

Nottingham City Hospital, Nottingham, UK

Daniel Harvey

Glangwili Hospital Child Health Section, Carmarthen, UK

Peter Havalda

Alder Hey Children’s Hospital, Liverpool, UK

Daniel B. Hawcutt

Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK

Antonia Y. W. Ho

Bronglais General Hospital, Aberystwyth, UK

Maria Hobrok

Worthing Hospital, Worthing, UK

Luke Hodgson

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Peter W. Horby

Rotheram District General Hospital, Rotheram, UK

Anil Hormis

Virology Reference Department, National Infection Service, Public Health England, Colindale Avenue, London, UK

Samreen Ijaz

Royal Free Hospital, London, UK

Michael Jacobs & Padmasayee Papineni

Homerton Hospital, London, UK

Airedale Hospital, Airedale, UK

Paul Jennings

Basildon Hospital, Basildon, UK

Agilan Kaliappan

The Christie NHS Foundation Trust, Manchester, UK

Vidya Kasipandian

University Hospital Lewisham, London, UK

Stephen Kegg

The Whittington Hospital, London, UK

Michael Kelsey

Southmead Hospital, Bristol, UK

Jason Kendall

Sheffield Childrens Hospital, Sheffield, UK

Caroline Kerrison

Royal United Hospital, Bath, UK

Ian Kerslake

Department of Pharmacology, University of Liverpool, Liverpool, UK

Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK

Paul Klenerman

Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Public Health Scotland, Edinburgh, UK

Susan Knight, Eva Lahnsteiner & Sarah Tait

Western General Hospital, Edinburgh, UK

Oliver Koch

Southend University Hospital NHS Foundation Trust, Southend-on-Sea, UK

Gouri Koduri

Hinchingbrooke Hospital, Huntingdon, UK

George Koshy & Tamas Leiner

Royal Preston Hospital, Fulwood, UK

Shondipon Laha

University Hospital (Coventry), Coventry, UK

Steven Laird

The Walton Centre, Liverpool, UK

Susan Larkin

ISARIC, Global Support Centre, COVID-19 Clinical Research Resources, Epidemic diseases Research Group, Oxford (ERGO), University of Oxford, Oxford, UK

James Lee & Daniel Plotkin

Centre for Health Informatics, Division of Informatics, Imaging and Data Science, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

Gary Leeming

Hull Royal Infirmary, Hull, UK

Patrick Lillie

Nottingham University Hospitals NHS Trust:, Nottingham, UK

Wei Shen Lim

Darlington Memorial Hospital, Darlington, UK

Queen Elizabeth Hospital (Gateshead), Gateshead, UK

Vanessa Linnett

Warrington Hospital, Warrington, UK

Jeff Little

Bristol Royal Hospital for Children, Bristol, UK

Mark Lyttle

St Mary’s Hospital (Isle of Wight), Isle of Wight, UK

Emily MacNaughton

The Tunbridge Wells Hospital, Royal Tunbridge Wells, UK

Ravish Mankregod

Huddersfield Royal, Huddersfield, UK

Countess of Chester Hospital, Liverpool, UK

Ruth McEwen & Lawrence Wilson

Frimley Park Hospital, Frimley, UK

Manjula Meda

Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK

Alexander J. Mentzer

Department of Microbiology/Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

Alison M. Meynert & Murray Wham

St James University Hospital, Leeds, UK

Jane Minton

Arrowe Park Hospital, Birkenhead, UK

Kavya Mohandas

Great Ormond Street Hospital, London, UK

Royal Shrewsbury Hospital, Shrewsbury, UK

Addenbrookes Hospital, Cambridge, UK

Elinoor Moore

Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

Shona C. Moore, William A. Paxton & Georgios Pollakis

East Surrey Hospital (Redhill), Redhill, UK

Patrick Morgan

Burton Hospital, Burton, UK

Craig Morris & Tim Reynolds

Peterborough City Hospital, Peterborough, UK

Katherine Mortimore

Kent and Canterbury Hospital, Canterbury, UK

Samuel Moses

Weston Area General Trust, Bristol, UK

Mbiye Mpenge

Bedfordshire Hospital, Bedfordshire, UK

Rohinton Mulla

Glasgow Royal Infirmary, Glasgow, UK

Michael Murphy

Macclesfield General Hospital, Macclesfield, UK

Thapas Nagarajan

Derbyshire Healthcare, Derbyshire, UK

Megan Nagel

Chelsea and Westminster Hospital, London, UK

Mark Nelson & Matthew K. O’Shea

Watford General Hospital, Watford, UK

Lillian Norris & Tom Stambach

EPCC, University of Edinburgh, Edinburgh, UK

Lucy Norris

Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, London, UK

Michael Olanipekun

Imperial College Healthcare NHS Trust: London, London, UK

Peter J. M. Openshaw

Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Anthonia Osagie

Prince Philip Hospital, Llanelli, UK

Igor Otahal & Andrew Workman

George Eliot Hospital – Acute Services, Nuneaton, UK

Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK

Carlo Palmieri

Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK

Kettering General Hospital, Kettering, UK

Selva Panchatsharam

University Hospitals of North Midlands NHS Trust, North Midlands, UK

Danai Papakonstantinou

Russells Hall Hospital, Dudley, UK

Hassan Paraiso

Harefield Hospital, Harefield, UK

Lister Hospital, Lister, UK

Natalie Pattison

Musgrove Park Hospital, Taunton, UK

Justin Pepperell

Kingston Hospital, Kingston, UK

Mark Peters

Queen’s Hospital, Romford, UK

Mandeep Phull

Southport and Formby District General Hospital, Southport, UK

Stefania Pintus

St George’s University of London, London, UK

Tim Planche

King’s College Hospital (Denmark Hill), London, UK

Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, School of Immunology and Microbial Sciences, King’s College London, London, UK

Nicholas Price

Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

The Clatterbridge Cancer Centre NHS Foundation, Bebington, UK

David Price

The Great Western Hospital, Swindon, UK

Rachel Prout

Ninewells Hospital, Dundee, UK

Nikolas Rae

Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK

Andrew Rambaut

Poole Hospital NHS Trust, Poole, UK

Henrik Reschreiter

William Harvey Hospital, Ashford, UK

Neil Richardson

King’s Mill Hospital, Sutton-in-Ashfield, UK

Mark Roberts

Liverpool Women’s Hospital, Liverpool, UK

Devender Roberts

Pinderfields Hospital, Wakefield, UK

Alistair Rose

North Devon District Hospital, Barnstaple, UK

Guy Rousseau

Queen Elizabeth Hospital, Birmingham, UK

Tameside General Hospital, Ashton-under-Lyne, UK

Brendan Ryan

City Hospital (Birmingham), Birmingham, UK

Taranprit Saluja

Department of Pediatrics and Virology, St Mary’s Medical School Bldg, Imperial College London, London, UK

Vanessa Sancho-Shimizu

The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK

Matthias Schmid

NHS Greater Glasgow and Clyde, Glasgow, UK

Janet T. Scott

Respiratory Medicine, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UK

Malcolm G. Semple

Broomfield Hospital, Broomfield, UK

Stoke Mandeville, UK

Prad Shanmuga

University Hospital of North Tees, Stockton-on-Tees, UK

Anil Sharma

Institute of Translational Medicine, University of, Liverpool, Merseyside, UK

Victoria E. Shaw

Royal Manchester Children’s Hospital, Manchester, UK

Anna Shawcross

New Cross Hospital, Wolverhampton, UK

Jagtur Singh Pooni

Bedford Hospital, Bedford, UK

Jeremy Sizer

Colchester General Hospital, Colchester, UK

Richard Smith

University Hospital Birmingham NHS Foundation Trust, Birmingham, UK

Catherine Snelson & Tony Whitehouse

Walton Centre NHS Foundation Trust, Liverpool, UK

Tom Solomon

Chesterfield Royal Hospital, Calow, UK

Nick Spittle

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK

Shiranee Sriskandan

Princess Alexandra Hospital, Harlow, UK

Nikki Staines & Shico Visuvanathan

Milton Keynes Hospital, Eaglestone, UK

Richard Stewart

Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

David Stuart

Royal Bolton Hopital, Farnworth, UK

Pradeep Subudhi

Department of Medicine, University of Cambridge, Cambridge, UK

Charlotte Summers

Department of Child Life and Health, University of Edinburgh, Edinburgh, UK

Olivia V. Swann

Royal Gwent (Newport), Newport, UK

Tamas Szakmany

The Royal Marsden Hospital (London), London, UK

Kate Tatham

Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK

Richard S. Tedder

Transfusion Microbiology, National Health Service Blood and Transplant, London, UK

Department of Medicine, Imperial College London, London, UK

Queen Victoria Hospital (East Grinstead), East Grinstead, UK

Leeds Teaching Hospitals NHS Trust, Leeds, UK

Robert Thompson

Royal Stoke University Hospital, Stoke-on-Trent, UK

Chris Thompson

Whiston Hospital, Rainhill, UK

Ascanio Tridente

Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, UK

Lance C. W. Turtle

Croydon University Hospital, Thornton Heath, UK

Mary Twagira

Gloucester Royal, Gloucester, UK

Nick Vallotton

West Hertfordshire Teaching Hospitals NHS Trust, Hertfordshire, UK

Rama Vancheeswaran

North Middlesex Hospital, London, UK

Rachel Vincent

Medway Maritime Hospital, Gillingham, UK

Lisa Vincent-Smith

Royal Papworth Hospital Everard, Cambridge, UK

Alan Vuylsteke

Derriford (Plymouth), Plymouth, UK

St Helier Hospital, Sutton, UK

Rachel Wake

Royal Berkshire Hospital, Reading, UK

Andrew Walden

Royal Liverpool Hospital, Liverpool, UK

Ingeborg Welters

Bradford Royal infirmary, Bradford, UK

Paul Whittaker

Central Middlesex, London, UK

Ashley Whittington

Royal Cornwall Hospital (Tresliske), Truro, UK

Meme Wijesinghe

North Bristol NHS Trust, Bristol, UK

Martin Williams

St. Peter’s Hospital, Runnymede, UK

Stephen Winchester

Leicester Royal Infirmary, Leicester, UK

Martin Wiselka

Grantham and District Hospital, Grantham, UK

Adam Wolverson

Aintree University Hospital, Liverpool, UK

Daniel G. Wootton

North Tyneside General Hospital, North Shields, UK

Bryan Yates

Queen Elizabeth Hospital, King’s Lynn, UK

Peter Young

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Contributions

F.L. recruited participants, acquired clinical samples, analyzed and interpreted data and cowrote the manuscript, including all drafting and revisions. C.E. analyzed and interpreted data and cowrote this manuscript, including all drafting and revisions. S.F. and M.R. supported the analysis and interpretation of data as well as drafting and revisions. D.S., J.K.S., S.C.M., S.A., N.M., J.N., C.K., O.C.L., O.E., H.J.C.M., A. Shikotra, A. Singapuri, M.S., V.C.H., M.T., N.J.G., N.I.L. and C.C. contributed to acquisition of data underlying this study. L.H.-W., A.A.R.T., S.L.R.-J., L.S.H., O.M.K., D.G.W., T.I.d.S. and A. Ho made substantial contributions to conception/design and implementation of this work and/or acquisition of clinical samples for this work. They have supported drafting and revisions of the manuscript. E.M.H., J.K.Q. and A.B.D. made substantial contributions to the study design as well as data access, linkage and analysis. They have supported drafting and revisions of this work. J.D.C., L.-P.H., A. Horsley, B.R., K.P., M.M. and W.G. made substantial contributions to the conception and design of this work and have supported drafting and revisions of this work. J.K.B. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, has made substantial contributions to conception and design of this work and has supported drafting and revisions of this work. M.G.S. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, sponsor/protocol chief investigator, has made substantial contributions to conception and design of this work and has supported drafting and revisions of this work. R.A.E. and L.V.W. are co-leads of PHOSP-COVID, made substantial contributions to conception and design of this work, the acquisition and analysis of data, and have supported drafting and revisions of this work. C.B. is the chief investigator of PHOSP-COVID and has made substantial contributions to conception and design of this work. R.S.T. and L.T. made substantial contributions to the acquisition, analysis and interpretation of the data underlying this study and have contributed to drafting and revisions of this work. P.J.M.O. obtained funding for ISARIC4C, is ISARIC4C consortium co-lead, sponsor/protocol chief investigator and has made substantial contributions to conception and design of this work. R.S.T. and P.J.M.O. have also made key contributions to interpretation of data and have co-written this manuscript. All authors have read and approve the final version to be published. All authors agree to accountability for all aspects of this work. All investigators within ISARIC4C and the PHOSP-COVID consortia have made substantial contributions to the conception or design of this study and/or acquisition of data for this study. The full list of authors within these groups is available in Supplementary Information .

Corresponding authors

Correspondence to Ryan S. Thwaites or Peter J. M. Openshaw .

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Competing interests.

F.L., C.E., D.S., J.K.S., S.C.M., C.D., C.K., N.M., L.N., E.M.H., A.B.D., J.K.Q., L.-P.H., K.P., L.S.H., O.M.K., S.F., T.I.d.S., D.G.W., R.S.T. and J.K.B. have no conflicts of interest. A.A.R.T. receives speaker fees and support to attend meetings from Janssen Pharmaceuticals. S.L.R.-J. is on the data safety monitoring board for Bexero trial in HIV+ adults in Kenya. J.D.C. is the deputy chief editor of the European Respiratory Journal and receives consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Janssen, Novartis, Pfizer and Zambon. A. Horsley is deputy chair of NIHR Translational Research Collaboration (unpaid role). B.R. receives honoraria from Axcella therapeutics. R.A.E. is co-lead of PHOSP-COVID and receives fees from AstraZenaca/Evidera for consultancy on LC and from AstraZenaca for consultancy on digital health. R.A.E. has received speaker fees from Boehringer in June 2021 and has held a role as European Respiratory Society Assembly 01.02 Pulmonary Rehabilitation secretary. R.A.E. is on the American Thoracic Society Pulmonary Rehabilitation Assembly program committee. L.V.W. also receives funding from Orion pharma and GSK and holds contracts with Genentech and AstraZenaca. L.V.W. has received consulting fees from Galapagos and Boehringer, is on the data advisory board for Galapagos and is Associate Editor for the European Respiratory Journal . A. Ho is a member of NIHR Urgent Public Health Group (June 2020–March 2021). M.M. is an applicant on the PHOSP study funded by NIHR/DHSC. M.G.S. acts as an independent external and nonremunerated member of Pfizer’s External Data Monitoring Committee for their mRNA vaccine program(s), is Chair of Infectious Disease Scientific Advisory Board of Integrum Scientific LLC, and is director of MedEx Solutions Ltd. and majority owner of MedEx Solutions Ltd. and minority owner of Integrum Scientific LLC. M.G.S.’s institution has been in receipt of gifts from Chiesi Farmaceutici S.p.A. of Clinical Trial Investigational Medicinal Product without encumbrance and distribution of same to trial sites. M.G.S. is a nonrenumerated member of HMG UK New Emerging Respiratory Virus Threats Advisory Group and has previously been a nonrenumerated member of the Scientific Advisory Group for Emergencies (SAGE). C.B. has received consulting fees and/or grants from GSK, AstraZeneca, Genentech, Roche, Novartis, Sanofi, Regeneron, Chiesi, Mologic and 4DPharma. L.T. has received consulting fees from MHRA, AstraZeneca and Synairgen and speakers’ fees from Eisai Ltd., and support for conference attendance from AstraZeneca. L.T. has a patent pending with ZikaVac. P.J.M.O. reports grants from the EU Innovative Medicines Initiative 2 Joint Undertaking during the submitted work; grants from UK Medical Research Council, GSK, Wellcome Trust, EU Innovative Medicines Initiative, UK National Institute for Health Research and UK Research and Innovation–Department for Business, Energy and Industrial Strategy; and personal fees from Pfizer, Janssen and Seqirus, outside the submitted work.

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Extended data

Extended data fig. 1 penalized logistic regression performance..

Graphs show classification error and Area under curve (AUC) from the 50 repeats tenfold nested cross-validation used to optimise and assess the performance of PLR testing associations with each LC outcome relative to Recovered (n = 233): Cardio_Resp (n = 398), Fatigue (n = 384), Anxiety/Depression (n = 202), GI (n = 132), ( e ) Cognitive (n = 6). The distributions of classification error and area under curve (AUC) from the nested cross-validation are shown. Box plot centre line represents the Median and boundaries of the box represent interquartile range (IQR), the whisker length represent 1.5xIQR.

Extended Data Fig. 2 Associations with long COVID symptoms in full study cohort.

( a ) Fibrinogen levels at 6 months were compared between pooled LC cases (n = 295) and Recovered (n = 233) and between the Cognitive group (n = 41) and Recovered (n = 233). Box plot centre line represent the Median and boundaries of the box represent interquartile range (IQR), the whisker length represents 1.5xIQR, any outliers beyond the whisker range are shown as individual dots. Median differences were compared using two-sided Wilcoxon signed-rank test *= p < 0·05, **= p < 0·01, ***= p < 0·001, ****= p < 0·0001. Unadjusted p-values are reported. b ) Distribution of time from COVID-19 hospitalisation at sample collection applying CDC and NICE definitions of LC (n = 719) ( c ) Upset plot of symptom groups. Horizontal coloured bars represent the number of patients in each symptom group: Cardiorespiratory (Cardio_Resp), Fatigue, Cognitive, Gastrointestinal (GI) and Anxiety/Depression (Anx_Dep). Vertical black bars represent the number of patients in each symptom combination group. To prevent patient identification, where less than 5 patients belong to a combination group, this has been represented as ‘<5’. The Recovered group (n = 250) were used as controls. Forest plots show Olink protein concentrations (NPX) associated with ( d ) Cardio_Resp (n = 398), ( e ) Fatigue (n = 342), ( f ) Anx_Dep (n = 219), ( g ) GI (n = 134), and ( h ) Cognitive (n = 65). Error bars represent the median accuracy of the model.

Extended Data Fig. 3 Validation of olink measurements using conventional assays in plasma.

Olink measured protein (NPX) were compared to chemiluminescence assays (ECL or ELISA, log2[pg/mL]) to validate our findings, where contemporaneously collected plasma samples were available (n = 58). Results from key mediators associated with LC groups were validated: CSF3, IL1R2, IL2, IL3RA, TNFa, TFF2. R = spearman rank correlation coefficient and shaded areas indicated the 95% confidence interval. Samples that fell below the lower limit of detection for a given assay were excluded and the ‘n’ value on each panel indicates the number of samples above this limit.

Extended Data Fig. 4 Univariate analysis of proteins associated with each symptom.

Olink measured plasma protein levels (NPX) compared between LC groups (Cardio_Resp, n = 398, Fatigue n = 384, Anxiety/Depression, n = 202, GI, n = 132 and Cognitive, n = 60) and Recovered (n = 233). Proteins identified by PLR were compared between groups. Median differences were compared using two-sided Wilcoxon signed-rank test. * = p < 0·05, ** = p < 0·01, *** = p < 0·001, ****= p < 0·0001 after FDR adjustment. Box plot centre line represent the Median and boundaries of the box represent interquartile range (IQR), the whisker length represents 1.5xIQR, any outliers beyond the whisker range are shown as individual dots.

Extended Data Fig. 5 Unadjusted Penalised Logistic Regression.

Olink measured proteins (NPX) and their association with Cardio_Resp (n = 398), Fatigue (n = 342), Anx_Dep (n = 219), GI (n = 134), and Cognitive (n = 65). Forest plots show odds of each LC outcome vs Recovered (n = 233), using PLR without adjusting for clinical co-variates. Error bars represent the median accuracy of the model.

Extended Data Fig. 6 Partial Least Squares analysis.

Olink measured proteins (NPX) and their association with Cardio_Resp (n = 398), Fatigue (n = 342), Anx_Dep (n = 219), GI (n = 134), and Cognitive (n = 65) groups. Forest plots show odds of LC outcome vs Recovered (n = 233), using PLS analysis. Error bars represent the standard error of the coefficient estimate.

Extended Data Fig. 7 Network analysis centrality.

Each graph shows the centrality score for each Olink measured protein (NPX) found to have significant associations with other proteins that were elevated in the Cardio_Resp (n = 398), Fatigue (n = 342), Anx_Dep (n = 219), GI (n = 134), and Cognitive (n = 65) groups relative to Recovered (n = 233).

Extended Data Fig. 8 Inflammation in men and women with long COVID.

Olink measured plasma protein levels (NPX) between men and women with symptoms, divided by age (<50 or >=50years): (a) shows IL1R2 and MATN2 in the Anxiety/Depression group (<50 n = 55, >=50 n = 133), (b) shows CTSO and NFASC in the Cognitive group (<50 n = 11, >=50 n = 50). Median values were compared between men and women using two-sided Wilcoxon signed-rank test. Box plot centre line represent the Median and boundaries represent interquartile range (IQR), the whisker length represents 1.5xIQR.

Extended Data Fig. 9 Inflammation in the upper respiratory tract.

Nasal cytokines measured by immunoassay in the CardioResp Group (n = 29) and Recovered (n = 31): ( a ) shows IL1a, IL1b, IL-6, APO-2, TGFa, TFF2. Median differences were compared using two-sided Wilcoxon signed-rank test. Box plot centre line represents the Median and boundaries of the box represent interquartile range (IQR), the whisker length represent 1.5xIQR. ( b ) Shows cytokines measured by immunoassay in paired plasma and nasal (n = 70). Correlations between IL1a, IL1b, IL-6, APO-2, TGFa and TFF2 in nasal and plasma samples were compared using Spearman’s rank correlation coefficient ( R ). Shaded areas indicated the 95% confidence interval of R.

Extended Data Fig. 10 Graphical abstract.

Summary of interpretation of key findings from Olink measured proteins and their association with CardioResp (n = 398), Fatigue (n = 342), Anx/Dep (n = 219), GI (n = 134), and Cognitive (n = 65) groups relative to Recovered (n = 233).

Supplementary information

Supplementary information.

Supplementary Methods, Statistics and reproducibility statement, Supplementary Results, Supplementary Tables 1–7, Extended data figure legends, Appendix 1 (Supplementary Table 8), Appendix 2 (PHOSP-COVID author list) and Appendix 3 (ISARIC4C author list).

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Liew, F., Efstathiou, C., Fontanella, S. et al. Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease. Nat Immunol 25 , 607–621 (2024). https://doi.org/10.1038/s41590-024-01778-0

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New long COVID study uncovers high inflammation in patients as Senate calls for more research on 'crisis'

The study followed 113 patients at four different hospitals in Switzerland.

A new study in Science is shining a light on the continuing impact of long COVID, with research revealing further and continuing health concerns for some of the 16 million sufferers in the U.S.

Long COVID is a syndrome, or collection of symptoms, that continue or develop after an acute COVID-19 infection and can last weeks, months or years. There is no test to confirm if symptoms are related to long COVID. Some scientists suggest that long COVID is caused by overactive immune cells, but the exact cause remains unclear.

The study followed 113 patients at four different hospitals in Switzerland with mild and severe COVID-19 and found that 40 had symptoms of long COVID at six months, 22 of whom had persistent symptoms at 12 months.

Researchers looked at blood samples from the 40 who experienced long COVID symptoms, compared them to controls who were not infected with COVID-19, and found that those who had long COVID had evidence of inflammation (increased complement activity), blood cell dysregulation (hemolysis and platelet activation) and tissue injury in their blood.

MORE: Long COVID research opens door for further exploration on post-viral illness

The specific details from the small study may help provide "a basis for new diagnostic solutions," according to the researchers, for the condition with no known cure or FDA-approved treatments.

While these results finding evidence of inflammation in patients with long COVID symptoms are not entirely surprising nor specific to long COVID, they are a step forward in identifying the cause of long COVID.

It's more than just researchers, though, looking into developments in our understanding of the syndrome. The condition received renewed attention from the federal government last week, as the U.S. Senate Committee on Health, Education, Labor and Pensions convened a group of patients and experts to testify about the impacts of long COVID before a bipartisan group of Senators.

PHOTO: Healthcare workers administer COVID-19 PCR test at a free test site in Farragut Square on Dec. 28, 2021, in Washington, D.C.

In the Senate's first-ever hearing on this topic, Sen. Tammy Baldwin said researchers and government officials need to "increase the sense of urgency" over understanding and treating the condition.

For Sen. Bernie Sanders, chairman of the committee, more needs to be done.

"We think we haven't done anywhere near enough, and we hope to turn that around," he said.

Medical experts testified at the hearing, telling the committee that the condition can emerge in patients of all ages and backgrounds, that the risk increases with multiple infections, and rates of long COVID are higher in minority communities.

"The burden of disease and disability from long COVID is on par with the burden of cancer and heart disease," Dr. Ziyad Al-Aly, M.D., a clinical epidemiologist at Washington University, said. "We must develop sustainable solutions to prevent repeated infections with SARS-CoV-2 and long COVID that would be embraced by the public."

Patients and Caregivers

Angela Meriquez Vazquez , a long COVID patient from California, testified that she has helped over 15,000 sufferers through online advocacy.

"We are living through the largest mass destabilizing event in modern history," she told the Senators.

MORE: America's gun violence problem by the numbers

As she told her own story, Meriquez Vazquez, a former runner, said she is currently on 12 medications. Although she said she has managed to continue working, and she has health care, the condition has forced her to work from home, lying down to minimize her symptoms.

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"Not since the emergence of the AIDS pandemic has there been such an imperative for large-scale change in healthcare, public health, and inequitable structures that bring exceptional risks of illness, suffering, disability, and mortality," Meriquez Vazzque said.

One of the Senators -- Republican Roger Marshall -- shared his own testimony, revealing to the committee that one of his loved ones "is one of the 16 million people" who has "suffered for two years" with the condition.

He told the committee his family member's illness is "like mono(nucleosis) that does not go away," adding that the person has seen 30 doctors in an attempt to find help.

Marshall said there needs to be more focus on treatments for long COVID at the Centers for Disease Control and Prevention.

"I'm frustrated that our CDC is more focused on vaccines than they are on treatments," he said.

Epidemiologists and Researchers weigh in

Dr. Al-Aly, while testifying, repeatedly called on our country's leaders and medical experts to come together to tackle the ongoing health crisis.

"We are the best nation on earth, and we can solve this," he said.

One of his proposed solutions is establishing a new multidisciplinary research institute to address infection-associated chronic conditions.

Research into the condition has been "slow," Dr. Charisse Madlock-Brown, Ph.D. from the University of Iowa, said at the hearing. She noted clinical trials are in the "experimental medicine" phase and pushed for more investment to identify proven treatments.

Sen. Tim Kaine said the National Institutes of Health has been provided more than $1 billion since 2020 to study long COVID, and he urged representatives from NIH to testify before the committee. In 2021, the NIH launched the Researching COVID to Enhance Recovery initiative to identify further risk factors and causes of long COVID.

"We can't take two years just to get 'geared up,'" he said.

According to the most recent information from the CDC , long COVID can cause up to 200 symptoms , including chronic fatigue, blood clots, gastrointestinal issues, brain fog and heart issues. Symptoms can last from months to years following a COVID infection. Risk factors for developing long COVID after a COVID-19 infection that have been identified include severe COVID-19 illness, underlying health conditions (such as asthma, diabetes, obesity or autoimmune diseases) and not getting the COVID-19 vaccine.

While the interest from the Senate and the new study in Science are promising, more research needs to be done to find the specific cause of why some people get long COVID from COVID-19, and others do not, and to find effective treatments.

Erin Hannon, MD, contributed to this report. Hannon is a resident physician in pediatrics from Columbia University/New York-Presbyterian Hospital, and a member of the ABC News Medical Unit.

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Scientists Offer a New Explanation for Long Covid

By Pam Belluck

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A team of scientists is proposing a new explanation for some cases of long Covid, based on their findings that serotonin levels were lower in people with the complex condition.

In their study , published on Monday in the journal Cell, researchers at the University of Pennsylvania suggest that serotonin reduction is triggered by remnants of the virus lingering in the gut. Depleted serotonin could especially explain memory problems and some neurological and cognitive symptoms of long Covid, they say.

A colored transmission electron micrograph shows an amorphous pink blob with a purple inner section that is its nucleus, with little green dots in the pink areas and a dark yellow background.

Why It Matters: New ways to diagnose and treat long Covid.

This is one of several new studies documenting distinct biological changes in the bodies of people with long Covid — offering important discoveries for a condition that takes many forms and often does not register on standard diagnostic tools like X-rays.

The research could point the way toward possible treatments, including medications that boost serotonin. And the authors said the biological pathway that their research outlines could unite many of the major theories of what causes long Covid: lingering remnants of the virus, inflammation, increased blood clotting and dysfunction of the autonomic nervous system.

“All these different hypotheses might be connected through the serotonin pathway,” said Christoph Thaiss, a lead author of the study and an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

“Second of all, even if not everybody experiences difficulties in the serotonin pathway, at least a subset might respond to therapies that activate this pathway,” he said.

“This is an excellent study that identifies lower levels of circulating serotonin as a mechanism for long Covid,” said Akiko Iwasaki, an immunologist at Yale University. Her team and colleagues at the Icahn School of Medicine at Mount Sinai recently published a study that identified other biological changes linked to some cases of long Covid, including levels of the hormone cortisol. These studies could point to specific subtypes of long Covid or different biological indicators at different points in the condition.

The Back Story: A series of disruptions set off by bits of virus in the gut.

Researchers analyzed the blood of 58 patients who had been experiencing long Covid for between three months and 22 months since their infection. Those results were compared to blood analysis of 30 people with no post-Covid symptoms and 60 patients who were in the early, acute stage of coronavirus infection.

Maayan Levy, a lead author and assistant professor of microbiology at the Perelman School of Medicine, said levels of serotonin and other metabolites were altered right after a coronavirus infection, something that also happens immediately after other viral infections.

But in people with long Covid, serotonin was the only significant molecule that did not recover to pre-infection levels, she said.

The team analyzed stool samples from some of the long Covid patients and found that they contained remaining viral particles. Putting the findings in patients together with research on mice and miniature models of the human gut, where most serotonin is produced, the team identified a pathway that could underlie some cases of long Covid.

Here’s the idea: Viral remnants prompt the immune system to produce infection-fighting proteins called interferons. Interferons cause inflammation that reduces the body’s ability to absorb tryptophan, an amino acid that helps produce serotonin in the gut. Blood clots that can form after a coronavirus infection may impair the body’s ability to circulate serotonin.

Depleted serotonin disrupts the vagus nerve system, which transmits signals between the body and the brain, the researchers said. Serotonin plays a role in short-term memory, and the researchers proposed that depleted serotonin could lead to memory problems and other cognitive issues that many people with long Covid experience.

“They showed that one-two-three punch to the serotonin pathway then leads to vagal nerve dysfunction and memory impairment,” Dr. Iwasaki said.

There are caveats. The study was not large, so the findings need to be confirmed with other research. Participants in some other long Covid studies, in which some patients had milder symptoms, did not always show depleted serotonin, a result that Dr. Levy said might indicate that depletion happened only in people whose long Covid involves multiple serious symptoms.

What’s Next: A clinical trial of Prozac.

Scientists want to find biomarkers for long Covid — biological changes that can be measured to help diagnose the condition. Dr. Thaiss said the new study suggested three: the presence of viral remnants in stool, low serotonin and high levels of interferons.

Most experts believe that there will not be a single biomarker for the condition, but that several indicators will emerge and might vary, based on the type of symptoms and other factors.

There is tremendous need for effective ways to treat long Covid, and clinical trials of several treatments are underway. Dr. Levy and Dr. Thaiss said they would be starting a clinical trial to test fluoxetine, a selective serotonin reuptake inhibitor often marketed as Prozac, and possibly also tryptophan.

“If we supplement serotonin or prevent the degradation of serotonin, maybe we can restore some of the vagal signals and improve memory and cognition and so on,” Dr. Levy said.

Pam Belluck is a health and science writer whose honors include sharing a Pulitzer Prize and winning the Victor Cohn Prize for Excellence in Medical Science Reporting. She is the author of “Island Practice,” a book about an unusual doctor. More about Pam Belluck

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HHS Announces the Formation of the Office of Long COVID Research and Practice and Launch of Long COVID Clinical Trials Through the RECOVER Initiative

C urrent analysis estimates that 7.7 million to 23 million Americans have developed Long COVID.

Today, U.S. Department of Health and Human Services (HHS) Secretary Xavier Becerra released the following statement applauding the formation of the Office of Long COVID Research and Practice to lead the Long COVID response and coordination across the federal government and, in addition, the National Institutes of Health (NIH) launch of the Long COVID clinical trials through the RECOVER Initiative.

“As our nation continues to make strides in combating COVID-19, it is crucial that we address the impact of Long COVID and provide resources to those in need,” said HHS Secretary Becerra. “Last year President Biden called on HHS to coordinate the response to Long COVID. The Official establishment of the Long COVID Coordinating office and the launch of the RECOVER clinical trials solidifies this issue as an ongoing priority.”

“The Office of Long COVID Research and Practice will enhance efforts being undertaken across the U.S. government to improve the lives of those who continue to experience the long-term impacts of the worst public health crisis in a century,” said Adm Rachel Levine, M.D. “Bringing together the resources and expertise of federal, state, and local partners, patients, providers, researchers, and the business sector to answer the American peoples most urgent calls to action.”

Background on the Office of Long COVID Research and Practice:

The Office of Long COVID Research will be located within HHS’s Office of the Assistant Secretary for Health under the leadership of the HHS Assistant Secretary for Health, Admiral Rachel Levine. The Office is charged with on-going coordination of the whole-of-government response to the longer-term effects of COVID-19, including Long COVID and associated conditions and the implementation of the National Research Action Plan on Long COVID and the Services and Supports for Longer-Term Impacts of COVID-19 . Currently 14 federal departments engage on Long COVID, including over a dozen HHS Operating and Staff Divisions with a goal to reduce the impacts of Long COVID by improving quality of life for people living with Long COVID and reducing disparities related to Long COVID.

Background on the RECOVER Initiative:

The NIH RECOVER Initiative is a $1.15 billion nationwide research program designed to understand, treat, and prevent long COVID, which describes long-term symptoms following infection by SARS-Cov-2, the virus that causes COVID-19. More than 200 symptoms are associated with long COVID, and the condition can cause problems throughout the body, affecting nearly all body systems including the nervous, cardiovascular, gastrointestinal, pulmonary, autonomic, and immune systems.

Launched in 2021, RECOVER established one of the largest, most diverse study group of patients with Long COVID in the world. The initial stage of the initiative involved launching large observational multi-site studies examining and following people through their experience with COVID-19 to learn why some people develop long-term symptoms while others recover completely. These studies are ongoing and have recruited more than 24,000 participants to date. Researchers also are analyzing 60 million electronic health records and conducting more than 40 pathobiology studies on how COVID-19 affects different body tissues and organs. This study cohort participated in RECOVER observational studies that allowed researchers to characterize the condition in great detail, which is critical for informing the development of clinical trials to test interventions. The clinical trials are designed so multiple treatments and therapies can be studied across five focus areas. Platform protocols for two of these areas were posted today, July 31, with enrollment for these trials beginning the end of July and throughout the summer. To learn more about the RECOVER clinical trials visit: https://trials.RECOVERCovid.org .

Through collaboration with federal partners, researchers, clinicians, patient advocacy organizations, and the business sector, the Biden-Harris Administration remains committed to addressing the longer-term impacts of the worst public health crisis in a century. We will continue to listen and learn from patients, caregivers, frontline workers, and those with lived experience, so we can accelerate understanding and breakthroughs together.

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Finally, scientists are making progress on long covid.

By Nancy Shute

Editor in Chief

March 31, 2024 at 7:15 am

New Long COVID Findings Offer Fuller Picture of Condition

Research published this week suggests that a test for long COVID could be possible.

Study: 1 in 14 Hit With Long COVID

FILE - A woman walks through a door with a sign asking shoppers to wear masks, in New York, Feb. 9, 2022. Information theft is on the rise. Frauds and scams often emerge during specific incidents such as the COVID pandemic, and in the wake of climate-related catastrophes. (AP Photo/Seth Wenig, File)

Seth Wenig | AP

A woman walks through a door with a sign asking shoppers to wear masks in New York on Feb. 9, 2022.

COVID-19 isn’t going away – and neither is long COVID. But new data about its prevalence as well as research into biomarkers of long COVID published this week are helping researchers understand what to look for when it comes to the condition.

Data published by the Centers for Disease Control and Prevention’s National Center for Health Statistics on Tuesday was a stark reminder that, while not widespread, some children are affected by long COVID.

Pulling from the 2022 National Health Interview Survey, the data shows that 1.3% of children ever had long COVID as of last year, according to reports from their parents.

The researchers defined long COVID as the “presence of symptoms for at least 3 months after having COVID-19 among those who received either a positive test or a doctor’s diagnosis of COVID-19.”

The rate of long COVID is significantly higher among adults than in children. The survey found that in 2022, about 7% of adults – or about 1 in 14 – reported ever having long COVID. More women reported having had long COVID than men – a trend also observed in children.

Adults ages 35-49 were most likely to have had long COVID, according to the data. Hispanic adults were more likely than Black and white adults to have it.

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The survey also found a higher prevalence of long COVID among Americans living in more rural areas compared with those living in large central metropolitan areas.

There are no approved treatments or tests for the condition. Its cause (or, more likely, causes) remains unknown, though studies have made some progress .

Research published Monday in the journal Nature found that people with long COVID have clear differences in their hormone and immune function when compared to people without the condition. The findings offer hope that a test for the condition is possible.

“These findings are important – they can inform more sensitive testing for long COVID patients and personalized treatments for long COVID that have, until now, not had a proven scientific rationale,” David Putrino, principal investigator of the study, said in a statement . “This is a decisive step forward in the development of valid and reliable blood testing protocols for long COVID.”

The study looked at survey results and blood samples from 270 individuals. It found that the blood of those experiencing long COVID had specific biomarkers, like abnormal T cell activity, reactivation of dormant viruses and low cortisol levels.

“These markers need to be validated in larger studies, but provide a first step in dissecting the disease pathogenesis of long COVID,” Akiko Iwasaki, co-principal investigator of the study, said in a statement.

Coronavirus metrics are increasing in the U.S., underscoring that COVID-19 – as well as long COVID – will be a lasting problem. Health officials have moved away from trying to prevent coronavirus infections, instead shifting their focus to preventing hospitalizations and deaths. Still, many Americans are dealing with repeat infections of COVID-19, which can come with increased risk for a myriad of health problems.

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Many people recover fully within a few days or weeks after being infected with SARS-CoV-2, the virus that causes COVID-19. However, others have symptoms that linger for weeks, months, or even years after their initial diagnosis. Some people seem to recover from COVID-19 but then see their symptoms return, or they develop different symptoms within a few months. Even people who had no symptoms when they were infected can develop them later. Either mild or severe COVID-19 can lead to long-lasting symptoms.

Long COVID, long-haul COVID, post-COVID-19 condition, chronic COVID, and post-acute sequelae of SARS-CoV-2 (PASC) are all names for the health problems that some people experience a few months after a COVID-19 diagnosis. Symptoms of Long COVID may be the same as or different than symptoms of COVID-19 . Long COVID can also trigger other health conditions such as diabetes or kidney disease.

For more information on Long COVID, check out these U.S. government resources:

National Institutes of Health (NIH)

Explore Long COVID information, news , and more on the COVID-19 research website
Learn about NIH’s RECOVER initiative and find clinical trials on Long COVID
Read how this NIH-funded RECOVER study developed a new symptom scoring system that will improve future Long COVID treatments
Read this NHLBI news story about how obstructive sleep apnea increases risks for Long COVID
Read this NHLBI news story about how lingering symptoms are common after COVID hospitalization
Read how an NIH-funded RECOVER study identified potential long COVID disparities
Read this NHLBI news story about how Long COVID may be less common in children
Read how an NHLBI-funded study found that exercise lags are common after Long COVID
Read this NIH Director’s Blog post about using artificial intelligence to advance the understanding of Long COVID
Read this NHLBI news story about how Long COVID impacts children.

Centers for Disease Control and Prevention (CDC)

Find tips for talking with your healthcare provider about Long COVID
Check out this fact sheet about caring for people living with post-COVID conditions

This White House fact sheet provides information about comprehensive government efforts to prevent, diagnose, and treat Long COVID.

Animation showing how COVID affects different parts of the human body

What are Long Covid Symptoms?

Check out this interactive graphic from NIH to learn how Long COVID affects different parts of the human body.

RECOVER Research Review (R3) Seminar Series

The NIH RECOVER initiative’s R3 Seminar Series promotes a shared understanding of the scientific research on Long COVID. This forum speeds up discovery by allowing experts to

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Study Uncovers Drivers of Lingering Symptoms in COVID-19 Long-haulers

Covid-19 patient.

A Yale-Duke collaborative research team may have identified some of the first biomarkers linked to impaired lung function in long-term COVID-19 patients.

Since the early months of the pandemic, scientists have tried to determine why some patients experience symptoms such as shortness of breath, cough, fever, fatigue, or chest pain weeks to months after their initial COVID-19 infection. What may drive or predict the persistence of long-term symptoms, also known as “post-acute sequelae of COVID-19,” remains poorly understood. A study published June 10 in the journal JCI Insight may provide answers about this mysterious condition.

The study, led by Hyung J. Chun, MD , an associate professor of cardiovascular medicine and pathology and co-director of the Yale Cardiovascular Research Center, examined the predictors of persistent illness.

“We wanted to get a better understanding of what is driving the disease process in patients who had persistent symptoms after their COVID-19 infection,” said Chun.

The researchers used patient data collected from the post-COVID-19 clinics to analyze whether the severity of the COVID-19 illness could impact the likelihood of persistent symptoms later — specifically worsening lung function — and if proteins in the blood were linked to increased likelihood of symptoms in post-COVID-19 patients.

Chun and the Yale team partnered with colleagues at Duke University School of Medicine for the study. The team enrolled 61 participants from post-COVID-19 clinics. The researchers used a pulmonary function test to track two key parameters for lung function, including the amount of air a person could exhale after taking a deep breath, and the ability to transfer inhaled oxygen from the lungs to the red blood cells.

We wanted to get a better understanding of what is driving the disease process in patients who had persistent symptoms after their COVID-19 infection. Hyung J. Chun, MD

The results showed that almost 70 percent of patients continued to report persistent difficulty breathing during their follow-up visits. The data also confirmed that those with more severe illness during their acute COVID infection were more likely to have impaired lung function at the time of the follow up.

Next, the team analyzed patients’ blood samples to identify biomarkers or biological markers that may be associated with persistent lung symptoms. They identified three proteins (lipocalin 2, matrix metalloproteinase 7, and hepatocyte growth factor) that were strongly associated with impaired lung function.

“These are markers of activation of a specific immune cell type called neutrophils, as well as factors that may promote lung injury when elevated. While we previously found them to be strongly associated with severe illness during acute COVID-19 illness, it is interesting that they appear to remain elevated in those who continue to have poor lung function during their recovery,” said Chun.

The findings support a Feb. 26 study published in the journal Blood Advances , where Chun and his colleagues discovered that lipocalin 2 and hepatocyte growth factors predicted which patients were more likely to suffer severe COVID-19 illness and require intensive care. Chun believes that these biomarkers may not only be associated with the severity of COVID-19 symptoms, but may also be driving the disease process — which could be targeted by future therapies.

The study’s co-authors are Alexander Pine, Alfred I. Lee, Vanessa Yu, and Marcus Shallow from the Yale School of Medicine, and Elias Coutavas, Coral X. Giovacchini, Anne Mathews, Brian Stephenson, Loretta G. Que, and Bryan D. Kraft of the Duke University School of Medicine.

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A new clue to the reason some people come down with long COVID

Max Barnhart

Protesters march outside the White House to call attention to those who have long COVID and those who have the disabling disease Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Nathan Posner/Anadolu Agency via Getty Images hide caption

Protesters march outside the White House to call attention to those who have long COVID and those who have the disabling disease Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Stéphanie Longet is an immunologist and a COVID researcher at the University of Saint-Etienne in France, and just like 10-20% of adults who were infected with the virus , she continues to have symptoms well after her infection has resolved – a condition known colloquially as long COVID.

"I got COVID one year ago and I developed some persistent symptoms," she says. "I cannot work too long. My legs are quickly exhausted. In the morning it feels like I had run a marathon during the night, and I didn't do anything, I just slept."

Longet and other scientists don't exactly know why some people develop long COVID while others don't, but preliminary research released in medRxiv in July suggests that genetics plays a role.

The new research, which was an international collaboration between dozens of scientists, describes how some people carry a version of a single gene, FOXP4 , that is associated with developing long COVID. Longet calls the new research an "important element" in understanding why some people's COVID symptoms seemingly never resolve.

A surprising finding about long COVID

Long COVID only affects a small percentage of people who are infected with SARS-CoV-2, but the scope of the pandemic means that many millions of people are suffering. Roughly 25 million people in the U.S. and over 17 million people in Europe have long COVID symptoms, with many more in other parts of the world.

There isn't a universally agreed upon definition for what is considered long COVID – people experience a range of different symptoms including "fatigue, muscle pain, intestinal disorders and brain fog" and for different periods of time according to Longet, who was not involved in the new research. That's made the disease difficult for scientists to fully understand.

But the new research adds to the growing body of work showing that genetics can influence COVID outcomes. It was only a few weeks ago when NPR reported that genetics might make some people resistant to developing any COVID symptoms at all.

Jill Hollenbach , an immunologist at the University of California, San Francisco, was one of the scientists who led the research on asymptomatic COVID. She says she was "surprised and excited" about the new long COVID findings.

"The fact that the authors were able to detect this association [between the FOXP4 gene and long COVID], I think, is spectacular," Hollenbach says.

Hollenbach also thinks that the new research on long COVID is refreshing because "there's a lot of frustration on the public's part around progress" of understanding the disease and how to treat it. "There can be a perception out there amongst some people who are involved in advocacy for long COVID that it's being dismissed [by the scientific community] and I don't think that's true."

The gene that may be connected

The new study looked at DNA from 6,450 people who developed long COVID and compared it to the DNA of those who did not. Not everyone who reported long COVID symptoms in the study had a clinical diagnosis so the research team used a broad definition of long COVID as self-reported symptoms of COVID that affect day-to-day life three months after the initial infection.

When that data was analyzed, only one connection between a person's genes and whether they developed long COVID stood out – the FOXP4 gene.

The FOXP4 gene is what biologists call a "transcription factor," meaning that it helps regulate processes throughout the body but isn't responsible for any one thing in particular. The new research shows that the gene is active in the lungs and mentions that other studies have found an association between FOXP4 and lung cancer.

However, the research does not point to FOXP4 as a smoking gun. "If you have the variant of FOXP4, in theory, you could have a higher probability to develop long COVID," Longet says. "But it doesn't mean if you have the variant that you will have long COVID."

Hollenbach, who published similar work on asymptomatic COVID in the journal Nature , says the new work is "methodologically extremely sound" and that "the result appears to be really clear."

But Hollenbach is also quick to point out that the genetic effect of the FOXP4 gene is relatively small – though that's not entirely surprising. "It's uncommon to see extremely strong genetic effects," she says. "What we find in studies like this gives us insights into what the underlying pathophysiology is."

The new research hints at "some underlying immune dysregulation in the lung itself," Hollenbach says, suggesting an abnormal immune response to COVID might be causing the long-term harm. "We need to just continue to follow these breadcrumbs and see where they lead us."

That might partially explain why so many people with long COVID are having lung problems, but for other common long COVID symptoms, like brain fog and fatigue, the activity of FOXP4 doesn't provide much of a clue, meaning there's more work to be done in order to understand all facets of the disease.

Why your genes may not fully dictate your COVID destiny

The latest research shows that there are clear connections between a person's genetics and how they respond to COVID. So does this mean that every individual's COVID fate was set in stone from the day they were born?

Hollenbach doesn't think so. "I don't believe that we are unnecessarily subjected to some kind of pre-destiny according to our genes," she says. "There's going to be many genetic and non-genetic factors that are going to be in play here."

One thing that Hollenbach says the scientific community agrees upon, and that this new research reinforces, is that, "you're more likely to have long COVID If you've had a very severe bout of COVID."

Which is why, according to Hollenbach, "vaccination is still our greatest tool" in the fight against COVID because it can prevent or reduce the severity of a COVID infection, reducing the chance someone develops long COVID.

In the meantime, however, there doesn't seem to be any imminent relief for those who are already dealing with the effects of long COVID. Longet suggests that people, "find different ways to organize your life. It's what I've done a little bit."

Working different hours, making diet modifications and trying light breathing exercises are all little things researchers have found to help manage symptoms .

Despite the lack of immediate help, Longet still believes that scientists will soon figure out a way to help resolve her symptoms and the symptoms of others with long COVID. "I'm hopeful because now there are quite a lot of studies and a lot of researchers who are working on this," she says. "I believe in science, so I'm quite hopeful."

Three studies spotlight long-term burden of COVID in US adults

Jikaboom / iStock

Three new studies shed new light on long COVID in the United States, with one finding that two thirds of severely ill patients reported persistent impairments for up to 1 year, another showing that US veterans were at three times the risk of preventable hospitalization in the month after infection, and the last revealing that one third of COVID-19 survivors had lingering symptoms at one time.

57% of very ill had persistent physical problems

Today in Critical Care Medicine , University of California San Francisco (UCSF) researchers describe their study of 156 critically ill COVID-19 patients transferred to long-term acute-care hospitals in Georgia, Kentucky, Nebraska, and Texas for weaning from ventilation and rehabilitation from March 2020 to February 2021.

Patients completed online or phone interviews 1 year after hospital release. The average patient age was 65, and average hospital stay was 2 months. Most spent an average of 1 month on mechanical ventilation and were healthy before their infection.

Of the 156 patients, almost two-thirds (64%) said they had a persistent impairment, including physical (57%), respiratory (49%), psychiatric (24%), and cognitive (15%) problems, 1 year later. Nearly half (47%) reported more than one type of impairment, and 19% still needed supplemental oxygen.

"We have millions of survivors of the most severe and prolonged COVID illness globally," first author Anil Makam, MD, said in a UCSF news release . "Our study is important to understand their recovery and long-term impairments, and to provide a nuanced understanding of their life-changing experience."

About 79% of patients said they hadn't fully recovered at 1 year, 99% were back at home, and 60% of the previously employed had returned to work. Many patients said they were more affected by hospital-related issues such as bedsores and nerve damage that limited use of their extremities than by COVID-related problems. Participants attributed improvement to exercise and rehabilitation, support, and time.

"The long-lasting impairments we observed are common to survivors of any prolonged critical illness, and not specific to COVID, and are best addressed through multidisciplinary rehabilitation," Makam said.

Veterans at much higher risk for 1 year

Today in JAMA Network Open , a team led by researchers from the Veterans Affairs (VA) Portland Health Care System in Oregon used an emulated-target randomized trial design with monthly sequential trials to compare the risk of potentially preventable hospitalization among COVID-infected veterans to those of matched uninfected controls.

The study enrolled 189,136 veterans diagnosed as having COVID-19 from March 2020 to April 2021 and 943,084 controls. The average patient age was 60.3 years, 89.1% were men, 69.4% were White, and 23.4% were Black. The primary outcome was a potentially preventable hospitalization at a VA facility, VA-purchased community care, or Medicare fee-for-service care.

"Delayed or inadequate treatment of ambulatory care–sensitive conditions (acute or chronic conditions that can be treated effectively through quality ambulatory care [ACSCs]) can result in hospitalization," the study authors wrote.

An increased risk of preventable hospitalization in veterans with SARS-CoV-2 ... highlights the need for research on ways in which SARS-CoV-2 shapes postinfection care needs and engagement with the health system.

"Thus, hospitalizations for ACSCs (hereinafter referred to as potentially preventable hospitalizations) are widely recognized as an indicator of ambulatory care access and quality. They are also increasingly used as a measure of health system performance during public health emergencies."

A total of 3.1% of participants (3.8% of COVID-19 survivors and 3.0% of controls) had a potentially preventable hospitalization during the 1-year follow-up. The risk of hospitalization was higher among COVID-19 survivors at 0 to 30 days (adjusted hazard ratio [AHR], 3.26), 0 to 90 days (AHR, 2.12), 0 to 180 days (AHR, 1.69), and 0 to 365 days (AHR, 1.44).

"In this cohort study, an increased risk of preventable hospitalization in veterans with SARS-CoV-2, which persisted for at least 1 year after initial infection, highlights the need for research on ways in which SARS-CoV-2 shapes postinfection care needs and engagement with the health system," the researchers wrote. "Solutions are needed to mitigate preventable hospitalization after SARS-CoV-2."

17 million adults currently have long COVID

Yesterday, KFF reported its latest long-COVID data, which show that rates of the condition have remained relatively steady for a year, suggesting that the burden will persist unless new methods of prevention and treatment are developed.

The data follow the March 2024 release of updated Centers for Disease Control and Prevention (CDC) COVID-19 recommendations, which don't instruct people to isolate after testing positive.

" The new CDC guidance brings a unified approach to the risks from respiratory viruses and reflects the nation’s progress against severe illness from COVID-19," wrote author Alice Burns, PhD, KFF associate director of the Program on Medicaid & Uninsured.

Although rates of long COVID have stabilized, the 17 million adults with long COVID may experience many employment and material hardships.

"However, as the nation moves further from the COVID-19 pandemic, rates of long COVID remain steady and 7% of all adults—roughly 17 million people—reported currently having long COVID in March 2024."

Among the findings:

Of adult COVID-19 survivors (60%), 3 in 10 report having long COVID at one time, and about 1 in 10 say they still have it.
Roughly 17 million adults currently have long COVID.
A total of 79% of adult with long COVID say their condition has limited their participation in activities, with 25% reporting it limits their activities "a lot."
Persistent symptoms occur most often among people who are transgender or have disabilities.
Regarding COVID-19 as just another respiratory virus may make accessing healthcare more difficult for groups disproportionately affected by persistent symptoms.
A total of 5% to 10% of adults may continue to have long COVID at any point, and research to improve diagnosis and treatment takes time.

"Although rates of long COVID have stabilized, the 17 million adults with long COVID may experience many employment and material hardships, with 4 in 10 reporting food insecurity, 2 in 10 reporting difficulty paying rent or mortgage, and 1 in 10 reporting that they had to stop working for a period of time because of their symptoms," Burns wrote.

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New Study Finds Potential Cause of Long COVID Symptoms—Experts Explain

Published Jan 23, 2024

Prevention Researchers say this could lead to diagnostic tests and treatments.

Long COVID has mystified the medical community for years, making it a tough condition to diagnose, let alone treat. However, a growing body of research has found more information on what may be behind long COVID , with the hope of eventually finding an effective treatment. Now, a new study has made an interesting discovery on what may cause long COVID symptoms : a change in the immune system that may be detected via a blood test.

That’s the major takeaway from a new study published in the journal Science . For the study, researchers followed 113 patients with COVID-19 and 39 healthy patients as controls. After six months, 40 of the COVID-19 patients developed symptoms of long COVID.

The researchers analyzed blood samples from those patients and found that they had a group of proteins that showed that a portion of the immune system called the complement system was ramped up well after the patients recovered from COVID-19.

The study analyzed 6,596 proteins across 268 blood samples, which were collected during patients’ acute phase and again six months later. Researchers found several differences in the blood of people with long COVID compared to the healthy patients, including an imbalance in proteins involved in blood clotting and inflammation. Researchers also found that those with long COVID had a group of proteins that showed that a portion of the immune system, called the complement system, was ramped up well after the patients recovered from COVID-19.

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. This definition of Long COVID was developed by the Department of Health and Human Services (HHS) in collaboration with CDC and other partners.

People call Long COVID by many names, including Post-COVID Conditions, long-haul COVID, post-acute COVID-19, long-term effects of COVID, and chronic COVID. The term post-acute sequelae of SARS CoV-2 infection (PASC) is also used to refer to a subset of Long COVID.

What You Need to Know

Long COVID is a real illness and can result in chronic conditions that require comprehensive care. There are resources available .
Long COVID can include a wide range of ongoing health problems; these conditions can last weeks, months, or years.
Long COVID occurs more often in people who had severe COVID-19 illness, but anyone who has been infected with the virus that causes COVID-19 can experience it.
People who are not vaccinated against COVID-19 and become infected may have a higher risk of developing Long COVID compared to people who have been vaccinated.
People can be reinfected with SARS-CoV-2, the virus that causes COVID-19, multiple times. Each time a person is infected or reinfected with SARS-CoV-2, they have a risk of developing Long COVID.
While most people with Long COVID have evidence of infection or COVID-19 illness, in some cases, a person with Long COVID may not have tested positive for the virus or known they were infected.
CDC and partners are working to understand more about who experiences Long COVID and why, including whether groups disproportionately impacted by COVID-19 are at higher risk.

In July 2021, Long COVID was added as a recognized condition that could result in a disability under the Americans with Disabilities Act (ADA). Learn more: Guidance on “Long COVID” as a Disability Under the ADA .

About Long COVID

Long COVID is a wide range of new, returning, or ongoing health problems that people experience after being infected with the virus that causes COVID-19. Most people with COVID-19 get better within a few days to a few weeks after infection, so at least 4 weeks after infection is the start of when Long COVID could first be identified. Anyone who was infected can experience Long COVID. Most people with Long COVID experienced symptoms days after first learning they had COVID-19, but some people who later experienced Long COVID did not know when they got infected.

There is no test that determines if your symptoms or condition is due to COVID-19. Long COVID is not one illness. Your healthcare provider considers a diagnosis of Long COVID based on your health history, including if you had a diagnosis of COVID-19 either by a positive test or by symptoms or exposure, as well as based on a health examination.

Science behind Long COVID

RECOVER: Researching COVID to Enhance Recovery

People with Long COVID may experience many symptoms.

People with Long COVID can have a wide range of symptoms that can last weeks, months, or even years after infection. Sometimes the symptoms can even go away and come back again. For some people, Long COVID can last weeks, months, or years after COVID-19 illness and can sometimes result in disability.

Long COVID may not affect everyone the same way. People with Long COVID may experience health problems from different types and combinations of symptoms that may emerge, persist, resolve, and reemerge over different lengths of time. Though most patients’ symptoms slowly improve with time, speaking with your healthcare provider about the symptoms you are experiencing after having COVID-19 could help determine if you might have Long COVID.

People who experience Long COVID most commonly report:

General symptoms ( Not a Comprehensive List)

Tiredness or fatigue that interferes with daily life
Symptoms that get worse after physical or mental effort (also known as “ post-exertional malaise ”)

Respiratory and heart symptoms

Difficulty breathing or shortness of breath
Fast-beating or pounding heart (also known as heart palpitations)

Neurological symptoms

Difficulty thinking or concentrating (sometimes referred to as “brain fog”)
Sleep problems
Dizziness when you stand up (lightheadedness)
Pins-and-needles feelings
Change in smell or taste
Depression or anxiety

Digestive symptoms

Stomach pain

Other symptoms

Joint or muscle pain
Changes in menstrual cycles

Symptoms that are hard to explain and manage

Some people with Long COVID have symptoms that are not explained by tests or easy to manage.

People with Long COVID may develop or continue to have symptoms that are hard to explain and manage. Clinical evaluations and results of routine blood tests, chest X-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other poorly understood chronic illnesses that may occur after other infections. People with these unexplained symptoms may be misunderstood by their healthcare providers, which can result in a delay in diagnosis and receiving the appropriate care or treatment.

Review these tips to help prepare for a healthcare provider appointment for Long COVID.

Health conditions

Some people experience new health conditions after COVID-19 illness.

Some people, especially those who had severe COVID-19, experience multiorgan effects or autoimmune conditions with symptoms lasting weeks, months, or even years after COVID-19 illness. Multi-organ effects can involve many body systems, including the heart, lung, kidney, skin, and brain. As a result of these effects, people who have had COVID-19 may be more likely to develop new health conditions such as diabetes, heart conditions, blood clots, or neurological conditions compared with people who have not had COVID-19.

People experiencing any severe illness may develop health problems

People experiencing any severe illness, hospitalization, or treatment may develop problems such as post-intensive care syndrome (PICS).

PICS refers to the health effects that may begin when a person is in an intensive care unit (ICU), and which may persist after a person returns home. These effects can include muscle weakness, problems with thinking and judgment, and symptoms of post-traumatic stress disorder (PTSD), a long-term reaction to a very stressful event. While PICS is not specific to infection with SARS-CoV-2, it may occur and contribute to the person’s experience of Long COVID. For people who experience PICS following a COVID-19 diagnosis, it is difficult to determine whether these health problems are caused by a severe illness, the virus itself, or a combination of both.

People More Likely to Develop Long COVID

Some people may be more at risk for developing Long COVID.

Researchers are working to understand which people or groups of people are more likely to have Long COVID, and why. Studies have shown that some groups of people may be affected more by Long COVID. These are examples and not a comprehensive list of people or groups who might be more at risk than other groups for developing Long COVID:

People who have experienced more severe COVID-19 illness, especially those who were hospitalized or needed intensive care.
People who had underlying health conditions prior to COVID-19.
People who did not get a COVID-19 vaccine.

Health Inequities May Affect Populations at Risk for Long COVID

Some people are at increased risk of getting sick from COVID-19 because of where they live or work, or because they can’t get health care. Health inequities may put some people from racial or ethnic minority groups and some people with disabilities at greater risk for developing Long COVID. Scientists are researching some of those factors that may place these communities at higher risk of getting infected or developing Long COVID.

Preventing Long COVID

The best way to prevent Long COVID is to protect yourself and others from becoming infected. For people who are eligible, CDC recommends staying up to date on COVID-19 vaccination , along with improving ventilation, getting tested for COVID-19 if needed, and seeking treatment for COVID-19 if eligible. Additional preventative measures include avoiding close contact with people who have a confirmed or suspected COVID-19 illness and washing hands or using alcohol-based hand sanitizer.

Research suggests that people who get a COVID-19 infection after vaccination are less likely to report Long COVID, compared to people who are unvaccinated.

CDC, other federal agencies, and non-federal partners are working to identify further measures to lessen a person’s risk of developing Long COVID. Learn more about protecting yourself and others from COVID-19 .

Living with Long COVID

Living with Long COVID can be hard, especially when there are no immediate answers or solutions.

People experiencing Long COVID can seek care from a healthcare provider to come up with a personal medical management plan that can help improve their symptoms and quality of life. Review these tips to help prepare for a healthcare provider appointment for Long COVID. In addition, there are many support groups being organized that can help patients and their caregivers.

Although Long COVID appears to be less common in children and adolescents than in adults, long-term effects after COVID-19 do occur in children and adolescents .

Talk to your doctor if you think you or your child has Long COVID. Learn more: Tips for Talking to Your Healthcare Provider about Post-COVID Conditions

Data for Long COVID

Studies are in progress to better understand Long COVID and how many people experience them.

CDC is using multiple approaches to estimate how many people experience Long COVID. Each approach can provide a piece of the puzzle to give us a better picture of who is experiencing Long COVID. For example, some studies look for the presence of Long COVID based on self-reported symptoms, while others collect symptoms and conditions recorded in medical records. Some studies focus only on people who have been hospitalized, while others include people who were not hospitalized. The estimates for how many people experience Long COVID can be quite different depending on who was included in the study, as well as how and when the study collected information. Estimates of the proportion of people who had COVID-19 that go on to experience Long COVID can vary.

CDC posts data on Long COVID and provides analyses, the most recent of which can be found on the U.S. Census Bureau’s Household Pulse Survey .

CDC and other federal agencies, as well as academic institutions and research organizations, are working to learn more about the short- and long-term health effects associated with COVID-19 , who gets them and why.

Scientists are also learning more about how new variants could potentially affect Long COVID. We are still learning to what extent certain groups are at higher risk, and if different groups of people tend to experience different types of Long COVID. CDC has several studies that will help us better understand Long COVID and how healthcare providers can treat or support patients with these long-term effects. CDC will continue to share information with healthcare providers to help them evaluate and manage these conditions.

CDC is working to:

Better identify the most frequent symptoms and diagnoses experienced by patients with Long COVID.
Better understand how many people are affected by Long COVID, and how often people who are infected with COVID-19 develop Long COVID
Better understand risk factors and protective factors, including which groups might be more at risk, and if different groups experience different symptoms.
Help understand how Long COVID limit or restrict people’s daily activity.
Help identify groups that have been more affected by Long COVID, lack access to care and treatment for Long COVID, or experience stigma.
Better understand the role vaccination plays in preventing Long COVID.
Collaborate with professional medical groups to develop and offer clinical guidance and other educational materials for healthcare providers, patients, and the public.

Caring for People with Post-COVID Conditions
Preparing for Appointments for Post-COVID Conditions
Researching COVID to Enhance Recovery
Guidance on “Long COVID” as a Disability Under the ADA

For Healthcare Professionals

Post-COVID Conditions: Healthcare Providers

Search for and find historical COVID-19 pages and files. Please note the content on these pages and files is no longer being updated and may be out of date.

Visit archive.cdc.gov for a historical snapshot of the COVID-19 website, capturing the end of the Federal Public Health Emergency on June 28, 2023.
Visit the dynamic COVID-19 collection to search the COVID-19 website as far back as July 30, 2021.

To receive email updates about COVID-19, enter your email address:

Exit Notification / Disclaimer Policy

The Centers for Disease Control and Prevention (CDC) cannot attest to the accuracy of a non-federal website.
Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.
You will be subject to the destination website's privacy policy when you follow the link.
CDC is not responsible for Section 508 compliance (accessibility) on other federal or private website.

COVID-19: Long-term effects

Some people continue to experience health problems long after having COVID-19. Understand the possible symptoms and risk factors for post-COVID-19 syndrome.

Most people who get coronavirus disease 2019 (COVID-19) recover within a few weeks. But some people — even those who had mild versions of the disease — might have symptoms that last a long time afterward. These ongoing health problems are sometimes called post- COVID-19 syndrome, post- COVID conditions, long COVID-19 , long-haul COVID-19 , and post acute sequelae of SARS COV-2 infection (PASC).

What is post-COVID-19 syndrome and how common is it?

Post- COVID-19 syndrome involves a variety of new, returning or ongoing symptoms that people experience more than four weeks after getting COVID-19 . In some people, post- COVID-19 syndrome lasts months or years or causes disability.

Research suggests that between one month and one year after having COVID-19 , 1 in 5 people ages 18 to 64 has at least one medical condition that might be due to COVID-19 . Among people age 65 and older, 1 in 4 has at least one medical condition that might be due to COVID-19 .

What are the symptoms of post-COVID-19 syndrome?

The most commonly reported symptoms of post- COVID-19 syndrome include:

Symptoms that get worse after physical or mental effort
Lung (respiratory) symptoms, including difficulty breathing or shortness of breath and cough

Other possible symptoms include:

Neurological symptoms or mental health conditions, including difficulty thinking or concentrating, headache, sleep problems, dizziness when you stand, pins-and-needles feeling, loss of smell or taste, and depression or anxiety
Joint or muscle pain
Heart symptoms or conditions, including chest pain and fast or pounding heartbeat
Digestive symptoms, including diarrhea and stomach pain
Blood clots and blood vessel (vascular) issues, including a blood clot that travels to the lungs from deep veins in the legs and blocks blood flow to the lungs (pulmonary embolism)
Other symptoms, such as a rash and changes in the menstrual cycle

Keep in mind that it can be hard to tell if you are having symptoms due to COVID-19 or another cause, such as a preexisting medical condition.

It's also not clear if post- COVID-19 syndrome is new and unique to COVID-19 . Some symptoms are similar to those caused by chronic fatigue syndrome and other chronic illnesses that develop after infections. Chronic fatigue syndrome involves extreme fatigue that worsens with physical or mental activity, but doesn't improve with rest.

Why does COVID-19 cause ongoing health problems?

Organ damage could play a role. People who had severe illness with COVID-19 might experience organ damage affecting the heart, kidneys, skin and brain. Inflammation and problems with the immune system can also happen. It isn't clear how long these effects might last. The effects also could lead to the development of new conditions, such as diabetes or a heart or nervous system condition.

The experience of having severe COVID-19 might be another factor. People with severe symptoms of COVID-19 often need to be treated in a hospital intensive care unit. This can result in extreme weakness and post-traumatic stress disorder, a mental health condition triggered by a terrifying event.

What are the risk factors for post-COVID-19 syndrome?

You might be more likely to have post- COVID-19 syndrome if:

You had severe illness with COVID-19 , especially if you were hospitalized or needed intensive care.
You had certain medical conditions before getting the COVID-19 virus.
You had a condition affecting your organs and tissues (multisystem inflammatory syndrome) while sick with COVID-19 or afterward.

Post- COVID-19 syndrome also appears to be more common in adults than in children and teens. However, anyone who gets COVID-19 can have long-term effects, including people with no symptoms or mild illness with COVID-19 .

What should you do if you have post-COVID-19 syndrome symptoms?

If you're having symptoms of post- COVID-19 syndrome, talk to your health care provider. To prepare for your appointment, write down:

When your symptoms started
What makes your symptoms worse
How often you experience symptoms
How your symptoms affect your activities

Your health care provider might do lab tests, such as a complete blood count or liver function test. You might have other tests or procedures, such as chest X-rays, based on your symptoms. The information you provide and any test results will help your health care provider come up with a treatment plan.

In addition, you might benefit from connecting with others in a support group and sharing resources.

Long COVID or post-COVID conditions. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html. Accessed May 6, 2022.
Post-COVID conditions: Overview for healthcare providers. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html. Accessed May 6, 2022.
Mikkelsen ME, et al. COVID-19: Evaluation and management of adults following acute viral illness. https://www.uptodate.com/contents/search. Accessed May 6, 2022.
Saeed S, et al. Coronavirus disease 2019 and cardiovascular complications: Focused clinical review. Journal of Hypertension. 2021; doi:10.1097/HJH.0000000000002819.
AskMayoExpert. Post-COVID-19 syndrome. Mayo Clinic; 2022.
Multisystem inflammatory syndrome (MIS). Centers for Disease Control and Prevention. https://www.cdc.gov/mis/index.html. Accessed May 24, 2022.
Patient tips: Healthcare provider appointments for post-COVID conditions. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/post-covid-appointment/index.html. Accessed May 24, 2022.
Bull-Otterson L, et al. Post-COVID conditions among adult COVID-19 survivors aged 18-64 and ≥ 65 years — United States, March 2020 — November 2021. MMWR Morbidity and Mortality Weekly Report. 2022; doi:10.15585/mmwr.mm7121e1.

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The Many Reasons for Hope in Long Covid

A cnn reporter's new book tells how long covid patients make democracy work..

Updated April 13, 2024 | Reviewed by Gary Drevitch

What Is a Career
Find a career counsellor near me
Long Covid patient-led innovations are changing the way healthcare is delivered.
Patient advocacy has led to political support for Long Covid research.
The new book "The Long Haul" is about the little guy finding a way to make democracy work to solve a problem.

To the millions of patients with Long Covid, who have lived with up to four years of debilitating or disabling symptoms, the disease is a disaster. Yet, in the midst of all the suffering, CNN Reporter Ryan Prior sees a story of community, advocacy, and democracy at its best. This week alone, U.S. Sen. Bernie Sanders has responded to the cries of Long Covid patients by announcing a legislative proposal for $10 billion in research funding for Long Covid over the next 10 years.

I talked with Prior, a fellow writer for Psychology Today , about his book, The Long Haul: How Long Covid Survivors Are Revolutionizing Health Care. In the book, Prior weaves his own life, the stories of activist patients, and the latest science into a captivating tale of regular people crying out for care that actually works. Scientists and public officials, who expected Covid-19 to be an infection that cleared up in a matter of weeks, were caught off guard by the tens of millions around the world who got sick and stayed sick. These Long Covid patients often found solace only with one another, organizing support groups across oceans and continents while ill in bed.

The Long Haul is now out in paperback from MIT Press.

Alison Escalante: Your own story was part of the inspiration for the book. What happened?

Ryan Prior: I got sick in 2006 on the weekend of my 17th birthday. I was a cross-country runner and a soccer player and taking AP classes. And then within two weeks, I had to drop out of school for about seven months. And I went to 16 different doctors who ultimately gave me the diagnosis of chronic fatigue syndrome. I attribute it to a tick-borne illness, likely Lyme disease due to a tick bite I had at a Boy Scout camp. I took 15 pills a day and got an IV infusion every month for about 12 years. But at this point I am entirely recovered, barring a relapse .

AE: What is the focus of your book and how has your view changed since it was published?

RP: I wanted to build the story around regular people who were able to stand up for a specific problem that they were having, and then to alert the powers that be to that problem: The story of regular citizens in a democracy to guide the process for how we solve problems. But when I finished this book in February 2022 I was dismayed, because I felt the story was half finished, and I really wanted to have a triumphal ending.

Even in the last few days, my feeling toward the book has changed because Senator Bernie Sanders, the Chair of the Senate Health, Education , Labor, and Pensions (HELP) Committee, has proposed a bill calling for the Long COVID moonshot and $10 billion over 10 years for research.

In 2021, I contacted Lisa McCorkell, and Hannah Davis from the Patient Led Research Collaborative to make them a part of this book showing how small groups of people can make a huge difference. Lisa wrote a piece in Nature, and then Sen. Sanders proposed the bill for the Long Covid Moonshot. It all proves my book’s underlying hypothesis: that when this huge number of people suffers, the powers that be can and do respond. And that makes me feel more optimistic ; this is what we learned in ninth-grade civics about how democracy is supposed to work.

AE: Is there bipartisan support for Long Covid research funding?

RP: Yes. There are two important Republicans on the HELP committee who are doctors. One of them is Kansas Senator Roger Marshall , who has a close loved one with Long COVID who has been to dozens of doctors, and been mostly bed-bound for a couple of years. Similarly, Louisiana Senator Bill Cassidy sees Long Covid as a very real problem and has called for research into solutions. The greatest amount of hope I have yet felt about Long COVID has happened in the last couple months.

AE: What have you seen in the last couple months that can give hope to patients?

RP: First, there’s a lot of phenomenal work being done in the startup world. For example, RTHM is a medical group designed to treat patients with Long Covid. I'm on the advisory board for a startup called COVID Blue Health, developing an AI -empowered virtual patient-centered care platform for patients with infection-associated chronic illness .

In the philanthropic sector, Vitalik Buterin, the co-founder the cryptocurrency Ethereum, is funding the Patient Led Research Collaborative. He’s also funding the Polybio Research Foundation , which is doing some incredible work on looking into the long-term effects of pathogens.

AE: How else are patients innovating ways to help themselves?

RP: With Long Covid comes despair and anguish. The severity of the symptoms and of the disability is exactly as bad as we [the pre-existing community with post-viral illnesses] had feared, especially for a specific subset of patients who are more moderate-to-severe and can't work anymore.

And there is also an exciting part: that so many people who have Long Covid are creatively building on the knowledge that that's largely been curated by patients with post-infectious Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS ). There is the generosity and willingness of patients to share their experience in online forums, which could be Slack, Facebook , Twitter, Reddit, etc. So many Long Covid patients know exactly what to expect, not because they've learned that from their doctors, but because they learned it from fellow patients. So there's a really important story here about peer-to-peer health.

When somebody gets a new diagnosis, they should be prescribed not just a treatment plan, but also be prescribed a peer support group who can walk them through it. This is how new Long Covid patients learn which supplement to put into your water for electrolytes, or what kind of compression stockings to wear and which brands are better or worse for dealing with postural orthostatic tachycardia syndrome (POTS). And those really specific aspects of patient wisdom are very important.

AE: What else are Long Covid patients doing to change health care?

RP: It’s been incredibly exciting to see patients creating startups, several of which involve using wearables to track and manage symptoms. Chicago-based Pathize is one of those groups. And Visible is a group that's run out of the UK, which has a lot of users on their platform. A community has evolved around these platforms, where patients can share data and compare what works for them. They are taking technology, and they're building new ways of doing research.

AE: What would you say to the naysayers who claim that Long Covid is psychosomatic? For example, some naysayers insist that support groups make things worse by “reinforcing an identity ." Others claim that the very act of measuring heart rate with a wearable causes anxiety and thus elevated heart rate.

RP: People who are well don't join support groups because they don't need them. Obviously, correlation doesn't guarantee causation. You could easily make a different inference based on that same data.

But for doctors struggling to separate these symptoms from anxiety or depression , there are numerous studies showing all kinds of different detectable objective data [that Long Covid is a biological disease]; for example, studies showing off-the-charts amounts of inflammation.

I think that some of the most important inferences come from the HIV doctors who come into Long Covid and see it under the exactly the same framework. You've got researchers who are veterans of looking at HIV, who are moving into the Long Covid world and translating all of their knowledge and finding similarities.

AE: What are your thoughts on Long Covid patient complaints about medical gaslighting ?

RP: Many health-care providers are under extreme pressure from the system that they are in to label something quickly, even if it's not correct, because of the lack of time that they have and the lack of tools that they have. And they have to figure out some other specialists to shuffle that patient onto. The number of options that the primary-care doctor has are severely limited and so patients get put into psychiatric areas due to the overall lack of knowledge.

Many patients rightly accused their doctors of gaslighting them. The other side of it is that many physicians are experiencing moral injury : When you see somebody suffering and you cannot do anything about it, that's traumatizing for doctors. As the actual possibilities for treating these patients increase, I hope to see better performance among health providers.

It takes 90 minutes to do a medical visit with a Long Covid patient, because of all the body systems involved. But if you could design a clinic where you've got the five or six relevant specialists, you can get it done in three hours.

AE: Is there a takeaway you'd like to leave with us?

RP: So many parts of these new ways of doing healthcare can be patient-centered and patient-led. There's an entirely new entrepreneurial ecosystem being built up, in addition to new ways of doing science. There really is hope for Long Covid patients and those with other post-infectious illnesses.

A pediatrician and writer, Dr. Escalante is on a mission to help parents out of the Shouldstorm that disconnects them from their kids. She is raising her own rambunctious boys.

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The tell-tale sign of long COVID—and 7 more common symptoms

Posted: March 22, 2024 | Last updated: March 22, 2024

<p>Most people who get infected with the coronavirus recover within a few weeks. However, some continue to experience symptoms weeks or even months after they are infected. They have what are known as <a href="https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html">long-haul symptoms of COVID-19</a>. As such, they are sometimes called COVID-19 long-haulers. Sometimes, even patients who had a mild or asymptomatic coronavirus infection can become long-haulers.</p> <p>Scientists want to learn more about who becomes a long-hauler and why. This knowledge can help shape public policy, and determine the best standards of care and precautions to prevent viral transmission of the disease.</p> <p>An advocacy group called Patient-Led Research for COVID-19 released its first <a href="https://docs.google.com/document/d/1KmLkOArlJem-PArnBMbSp-S_E3OozD47UzvRG4qM5Yk/edit">report</a> in May 2020, to provide an in-depth look at the experiences of more than 600 COVID-19 long-haulers. Susannah Fox, who studies online communities of patients with chronic conditions, told <a href="https://www.technologyreview.com/2020/08/12/1006602/covid-19-long-haulers-are-organizing-online-to-study-themselves/">MIT Technology Review</a> in August 2020 that such patient groups will be more important to health professionals, particularly during crises such as the coronavirus, that cause health professionals to be overwhelmed.</p> <p>"The future of health care and technology is being built on such communities," Fox said. She added that some of the earliest users of online bulletin boards and other online communities were patients with chronic diseases.</p> <p>Stacker compiled a list of long-term COVID-19 symptoms based on research and data from experts at institutions across the world, including the Centers for Disease Control and Prevention, Mayo Clinic, Northwestern University, and New York-Presbyterian/Columbia University.</p>

Eight long-haul symptoms of COVID-19

Most people who get infected with the coronavirus recover within a few weeks. However, some continue to experience symptoms weeks or even months after they are infected. They have what are known as long-haul symptoms of COVID-19 . As such, they are sometimes called COVID-19 long-haulers. Sometimes, even patients who had a mild or asymptomatic coronavirus infection can become long-haulers.

Scientists want to learn more about who becomes a long-hauler and why. This knowledge can help shape public policy, and determine the best standards of care and precautions to prevent viral transmission of the disease.

An advocacy group called Patient-Led Research for COVID-19 released its first report in May 2020, to provide an in-depth look at the experiences of more than 600 COVID-19 long-haulers. Susannah Fox, who studies online communities of patients with chronic conditions, told MIT Technology Review in August 2020 that such patient groups will be more important to health professionals, particularly during crises such as the coronavirus, that cause health professionals to be overwhelmed.

"The future of health care and technology is being built on such communities," Fox said. She added that some of the earliest users of online bulletin boards and other online communities were patients with chronic diseases.

Stacker compiled a list of long-term COVID-19 symptoms based on research and data from experts at institutions across the world, including the Centers for Disease Control and Prevention, Mayo Clinic, Northwestern University, and New York-Presbyterian/Columbia University.

<p>Among 100 people who presented to Northwestern Memorial Hospital's <a href="https://onlinelibrary.wiley.com/doi/10.1002/acn3.51350">Neuro-COVID-19 clinic</a> in Chicago, with symptoms compatible with the Infectious Diseases Society of America COVID-19 guidelines, 59% reported dysgeusia, or an impaired sense of taste, and 55% reported anosmia, or an altered sense of smell. The patients were seen at the hospital, which operates in a partnership with Northwestern University's Feinberg School of Medicine, an average of five to six months after the onset of COVID-19 symptoms. Dysgeusia and anosmia may be the result of viral invasion of the olfactory cortex, the part of the brain associated with the sense of smell and taste.</p>

Altered sense of smell and taste

Among 100 people who presented to Northwestern Memorial Hospital's Neuro-COVID-19 clinic in Chicago, with symptoms compatible with the Infectious Diseases Society of America COVID-19 guidelines, 59% reported dysgeusia, or an impaired sense of taste, and 55% reported anosmia, or an altered sense of smell. The patients were seen at the hospital, which operates in a partnership with Northwestern University's Feinberg School of Medicine, an average of five to six months after the onset of COVID-19 symptoms. Dysgeusia and anosmia may be the result of viral invasion of the olfactory cortex, the part of the brain associated with the sense of smell and taste.

Difficulty breathing

Dyspnea, or difficulty breathing, is the most common long-haul symptom of COVID-19. More than 40% to almost 70% of patients with COVID-19 report having trouble breathing 60 to 100 days after diagnosis or hospitalization. Dyspnea has been linked to viral damage of the alveolar and epithelial cells in the lungs, and inflammatory damage to vascular cells. Researchers have found corticosteroids may help some long-haul COVID-19 patients with residual lung inflammation or persistent inflammatory interstitial lung disease.

<p><a href="https://www.nature.com/articles/s41591-021-01283-z">Cognitive impairment</a> after COVID-19 recovery can present as trouble with concentration, memory, understanding words and language, and/or executive function. These cognitive difficulties may be the result of damage to the hippocampus, the part of the brain that plays an important role in learning and memory. Damage to the hippocampus may put people with COVID-19 long-haul symptoms at risk for the hippocampal-related degeneration characteristic of Alzheimer's disease.</p>

Memory issues

Cognitive impairment after COVID-19 recovery can present as trouble with concentration, memory, understanding words and language, and/or executive function. These cognitive difficulties may be the result of damage to the hippocampus, the part of the brain that plays an important role in learning and memory. Damage to the hippocampus may put people with COVID-19 long-haul symptoms at risk for the hippocampal-related degeneration characteristic of Alzheimer's disease.

<p>The coronavirus that causes COVID-19 can make blood cells more likely to <a href="https://www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/coronavirus-long-term-effects/art-20490351">coagulate</a>, or clump and form clots. Specifically, heart damage caused by COVID-19 is likely the result of clots in the small vessels, or capillaries, in the heart. The risk of blood clots in those with long-haul COVID-19 may be associated with damage from severe inflammation, although scientists don't know how long the inflammation can persist. Doctors might want to treat blood clots in those with long-haul COVID-19 with low-molecular weight heparin and direct oral anticoagulants versus <a href="https://www.nature.com/articles/s41591-021-01283-z">vitamin K antagonists</a>, because patients taking vitamin K antagonists need frequent blood tests to monitor medication levels.</p>

More frequent blood clots

The coronavirus that causes COVID-19 can make blood cells more likely to coagulate , or clump and form clots. Specifically, heart damage caused by COVID-19 is likely the result of clots in the small vessels, or capillaries, in the heart. The risk of blood clots in those with long-haul COVID-19 may be associated with damage from severe inflammation, although scientists don't know how long the inflammation can persist. Doctors might want to treat blood clots in those with long-haul COVID-19 with low-molecular weight heparin and direct oral anticoagulants versus vitamin K antagonists , because patients taking vitamin K antagonists need frequent blood tests to monitor medication levels.

<p>Patients with long-haul COVID-19 may develop or will continue to experience neuropsychiatric symptoms, including insomnia, or sleeplessness, for months after they are initially infected. These symptoms may be the result of <a href="https://www.nature.com/articles/s41591-021-01283-z">nerve cell damage due to inflammation</a>. Levels of immune system activation are directly associated with cognitive and behavioral changes. Although little compelling evidence exists that the coronavirus that causes COVID-19 infects neurons, autopsies have found evidence that the virus causes changes in the brain that promote inflammation in nerve cells and blood vessels in the brain. Inflammaging, the chronic low-level brain inflammation that develops with age, may also play a role in the persistent psychiatric effects of COVID-19.</p>

Trouble sleeping

Patients with long-haul COVID-19 may develop or will continue to experience neuropsychiatric symptoms, including insomnia, or sleeplessness, for months after they are initially infected. These symptoms may be the result of nerve cell damage due to inflammation . Levels of immune system activation are directly associated with cognitive and behavioral changes. Although little compelling evidence exists that the coronavirus that causes COVID-19 infects neurons, autopsies have found evidence that the virus causes changes in the brain that promote inflammation in nerve cells and blood vessels in the brain. Inflammaging, the chronic low-level brain inflammation that develops with age, may also play a role in the persistent psychiatric effects of COVID-19.

<p>Dizziness, sometimes called vertigo, has long been associated with <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492824/">viral infections</a>. So researchers are not really surprised that studies from around the world have found vertigo is one of the most common symptoms of COVID-19. Scientists in Pakistan believe that the coronavirus enters the nervous system via the circulatory system, and binds to the <a href="https://pubs.acs.org/doi/10.1021/acschemneuro.0c00122">angiotensin-converting enzyme 2 receptors</a> in the lining of the capillaries in the brain. Hypoxia, or insufficient oxygen delivery, and damage caused by blood clots and inflammation are other possible ways nervous system damage can cause vertigo in those with long-haul COVID-19.</p>

Lightheadedness

Dizziness, sometimes called vertigo, has long been associated with viral infections . So researchers are not really surprised that studies from around the world have found vertigo is one of the most common symptoms of COVID-19. Scientists in Pakistan believe that the coronavirus enters the nervous system via the circulatory system, and binds to the angiotensin-converting enzyme 2 receptors in the lining of the capillaries in the brain. Hypoxia, or insufficient oxygen delivery, and damage caused by blood clots and inflammation are other possible ways nervous system damage can cause vertigo in those with long-haul COVID-19.

<p>Scientists do not know much about what causes post-COVID-19 fatigue, also called <a href="https://www.cdc.gov/me-cfs/healthcare-providers/clinical-care-patients-mecfs/treating-most-disruptive-symptoms.html#:~:text=Post-exertional%20malaise%20%28PEM%29%20is%20the%20worsening%20of%20symptoms,and%20illness%20relapses%20by%20balancing%20rest%20and%20activity.">post-exertional malaise</a> or chronic fatigue/myalgic encephalopathy, following viral infection. One possible explanation is that while the body fights off the coronavirus, the immune system releases proteins that promote inflammation and can stimulate the immune response. These proteins are called cytokines, and they are also responsible for the symptoms of post-COVID-19 fatigue. However, cytokine levels sometimes do not return to normal and cause ongoing symptoms.</p>

Strain after physical or mental work

Scientists do not know much about what causes post-COVID-19 fatigue, also called post-exertional malaise or chronic fatigue/myalgic encephalopathy, following viral infection. One possible explanation is that while the body fights off the coronavirus, the immune system releases proteins that promote inflammation and can stimulate the immune response. These proteins are called cytokines, and they are also responsible for the symptoms of post-COVID-19 fatigue. However, cytokine levels sometimes do not return to normal and cause ongoing symptoms.

<p>Viral infection, inflammation and the immune response, and a decrease in the number of, or downregulation of, angiotensin-converting enzyme 2 receptors may be the root cause of <a href="https://www.nature.com/articles/s41591-021-01283-z">chest pain and heart palpitations</a> in those with long-haul COVID-19. Infection, inflammation, and the downregulation of ACE2 receptors damage the heart muscle; the pericardium, or the sac around the heart; and the conduction system that controls the heartbeat by conducting electrical impulses through the heart. Scarring of the heart muscle can lead to palpitations, or arrhythmias, as can cytokines, which are proteins that stimulate the immune response and promote inflammation.</p>

Chest pain and heart palpitations

Viral infection, inflammation and the immune response, and a decrease in the number of, or downregulation of, angiotensin-converting enzyme 2 receptors may be the root cause of chest pain and heart palpitations in those with long-haul COVID-19. Infection, inflammation, and the downregulation of ACE2 receptors damage the heart muscle; the pericardium, or the sac around the heart; and the conduction system that controls the heartbeat by conducting electrical impulses through the heart. Scarring of the heart muscle can lead to palpitations, or arrhythmias, as can cytokines, which are proteins that stimulate the immune response and promote inflammation.

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IMAGES

Long-Haul COVID: Overview, Differences, and Treatment
Long Haulers: Symptoms, Treatments & Understanding After Effects of
Long Haul COVID Outcomes
The COVID Long Haul: Stories of patients and possible treatments
Long COVID
FAQs: Long Haul Syndrome

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