USA: The RECOVER Initiative - Long Covid research

Andy said:
This was published on the NIH's Director's blog.

"Understanding Long-Term COVID-19 Symptoms and Enhancing Recovery

We are in the third year of the COVID-19 pandemic, and across the world, most restrictions have lifted, and society is trying to get back to “normal.” But for many people—potentially millions globally—there is no getting back to normal just yet.

They are still living with the long-term effects of a COVID-19 infection, known as the post-acute sequelae of SARS-CoV-2 infection (PASC), including Long COVID. These people continue to experience debilitating fatigue, shortness of breath, pain, difficulty sleeping, racing heart rate, exercise intolerance, gastrointestinal and other symptoms, as well as cognitive problems that make it difficult to perform at work or school.

This is a public health issue that is in desperate need of answers. Research is essential to address the many puzzling aspects of Long COVID and guide us to effective responses that protect the nation’s long-term health.

For the past two years, NIH’s National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Allergy and Infectious Diseases (NIAID), and my National Institute of Neurological Disorders and Stroke (NINDS) along with several other NIH institutes and the office of the NIH Director, have been leading NIH’s Researching COVID to Enhance Recovery (RECOVER ) initiative, a national research program to understand PASC."

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"It is important to note that post-viral conditions are not a new concept. Many, but not all, of the symptoms reported in Long COVID, including fatigue, post-exertional malaise, chronic musculoskeletal pain, sleep disorders, postural orthostatic tachycardia (POTS), and cognitive issues, overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

ME/CFS is a serious disease that can occur following infection and make people profoundly sick for decades. Like Long COVID, ME/CFS is a heterogenous condition that does not affect everybody in the same way, and the knowledge gained through research on Long COVID may also positively impact the understanding, treatment, and prevention of POTS, ME/CFS, and other chronic diseases."

https://directorsblog.nih.gov/2022/...erm-covid-19-symptoms-and-enhancing-recovery/
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I appreciate the blog but we need action as this is the reality for ME/CFS:

 
Oh, for sure. I stand by my original comment--I'm very proud the NIH and CDC speak of ME/CFS as a serious problem. But there's not enough action. They're consulting experts in post-viral syndromes in the RECOVER trial, publishing good material about ME, and funding some research. That's good, but we need far more.
 
Keynote Presentation: Advancing Toward Recovery from Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): The NIH RECOVER Initiative with Live Q&A


OCT 19, 2022 12:00 PM PDT

Walter Koroshetz, MD
Director of the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health
Abstract
The COVID-19 pandemic has affected the lives of most Americans. The consequences on the future health of the nation are unknown but likely profound. Well known is the condition known in the lay press as “Long Covid” which leads to persistent clusters of symptoms in a significant proportion of persons for prolonged periods after the acute infection. These clusters are quite similar to those presented by persons suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) for decades, some of whom identify an infectious-like illness as the trigger for their condition; ie., Lyme disease, infectious mononucleosis. The underlying biology of Long Covid and ME/CFS is a mystery. The RECOVER Initiative was designed to launch a comprehensive program to identify the pathophysiologic basis of Post Acute Sequelae of COVID-19 and to test treatments that might reduce the suffering due to Long Covid as well as other future health complications of the pandemic. RECOVER includes a large natural history study of good vs. poor recovery after COVID with a tiered series of successive investigations customized to the different symptom clusters. In addition, RECOVER includes electronic health record studies with access to 60 million patient records, and an autopsy study to examine tissues in hundreds who have died of any cause in the months after infection. RECOVER is also designing master protocols for treatments aimed at reducing symptoms as well as potential causative pathophysiologic processes such as persistent viral infection, autoimmunity, immune dysregulation etc.

Learning Objectives:

1. Discuss the spectrum of post-acute sequelae of COVID-19 infection.

2. Recognize the similarities between what is now termed “Long-Covid” and other post viral illnesses classified as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

3. Discuss the NIH’s RECOVER Initiative to advance knowledge of the biologic basis of “Long Covid” and other sequelae of the pandemic.
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register at link
https://www.labroots.com/webinar/ke...elae-sars-cov-2-infection-pasc-nih-recover-in
 
ARUP’s Clinical Trials Group Assists in Multisite Study Aimed at Unravelling the Mysteries of Long COVID-19

Patients connecting in online forums such as O’Brien’s across the country helped to spur the creation of the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Initiative. According to the NIH RECOVER team, the initiative seeks to quickly improve our understanding of recovery after SARS-CoV-2 infection and to prevent and treat long-term health effects.

The NIH granted the parent award to New York University (NYU) Langone Health, which in turn has made multiple subawards to more than 100 investigators at 30 different institutions. ARUP Laboratories is contracted with NYU as a RECOVER Core, meaning that ARUP provides centralized laboratory testing for 150 partner sites.

The NIH RECOVER team explained that the primary role of RECOVER Core centers is to build and support the RECOVER Initiative and its participant pool and team of investigators, and to ensure that data are standardized and effectively shared among researchers and with the public. By working in tandem with researchers across the country, ARUP plays an integral role in helping investigators understand why some people recover from COVID-19 while others, like O’Brien, do not. This work is expected to shed light on other postacute infection syndromes, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
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full article
https://www.aruplab.com/magnify22/arups-clinical-trials-group-assists-multisite-study-long-covid-19
 
Summary


  • The RECOVER Initiative has spent hundreds of millions of dollars building out the infrastructure to support its big study – following and analyzing 18,000 people.
  • Grants from outside researchers, though, are important as well. The vast majority of potential long COVID researchers, after all, reside outside the RECOVER Initiative and they can provide creative insights that Initiative investigators might miss.
  • In August RECOVER released the titles of the 40 grants it funded to the tune of $37 million dollars. This blog assessed them for their potential impact on the ME/CFS subset of long COVID and ME/CFS itself.
  • Because, strangely enough, almost all the grants do not show up in the NIH’s Reporter database of NIH-funded studies, much detail was missed.
  • It was hard understanding how 15% of the grants met the definition of a long COVID grant. A further 24% of the grants focused on the non-ME/CFS subset of long COVID (such as diabetes, kidney disease, etc.). About 60% of the grants clearly focused on the ME/CFS subset of long COVID.
  • As expected immune system grants lead the pack and the strong focus on autoantibodies was welcome. EBV reactivation has shown up in several major studies but unfortunately was assessed in only one. The blood vessels and cardiovascular system, and the metabolism – two areas the NIH might have passed on – received good interest – as did the nervous system and brain.
  • Surprisingly, the autonomic nervous system – obviously a key player in long COVID – received only one study. Unfortunately, no exercise physiology studies – so important to the field of ME/CFS – were funded. Neither were any microbiome or mitochondrial studies.
  • Overall, the slate of studies seemed strong but the number of studies being funded and the amount of funding devoted to them, though, was surprisingly low. RECOVER is a $1.15 billion Initiative yet it provided all of $40 million to individual research projects – just 2 1/2 times the funding ME/CFS gets in a year.
  • Why that was so and other questions have been forwarded to the RECOVER Initiative.
 
I have been really concerned about what the RECOVER programme has been funding for a while. Initially they were funding absolutely nothing but data collection, the entire thing was just the biggest symptom and fluids collection study in the entire world of all time, a true master use of 500 million USD. But now it seems the little over half of the rest of it is being aimed at research and I am not surprised to find a lot of it is barely applicable to the disease itself. I sure hope they come up with something but they have I think avoided the most promising areas of research so far so I don't anticipate much of value coming out of it.
 
I find the Health Rising piece confusing - it seems to require that: the long term effects of COVID 19 substantially = Long Covid and that in turn Long COVID substantially = ME/CFS, when no part of that line of equivalences has so far been shown to have significance.

From a public health perspective, which is what surely the US Congress had in its collective mind when it required the NIH to commit $1.15 billion to studying the long-term effects of COVID, all health consequences of COVID infection would require attention, and which includes a vast range of sequelae only a fraction of which are common to an ME/CFS diagnosis. The COVID19 pandemic may as a simple fact of itself, require greater investigation of ME/CFS but so far none of the epidemiology strongly indicates that there is a major increase in ME/CFS incidence following COVID19 infection.

I know that's not what many people expect and there may be all sorts of failings that mean post COVID ME/CFS incidence is not being recognised or recorded, but for whatever reason it isn't there strongly in the data while all sorts of other health problems are and it's not surprising if those are attracting research funding rather than ME/CFS.
 
But there are funded projects that are not related to the long-term effects of Covid, apart from the MECFS subset.


The Strange – Long COVID Grants (???) – 14%
I would be shocked if Congress had these studies in mind when it funded the RECOVER project. It’s possible that some of these studies added long COVID cohorts to ongoing studies. Still, they seem like a reach.

  • Elucidating Genetic and Environmental Second Hits in Racial and Ethnic Minorities with APOL1 High-Risk Genotypes – this is a kidney disease study that was ongoing before COVID-19 and does not mention long COVID
  • Imaging Neuroglial Mechanisms of Neuropathic Pain-Opioid Interaction in HIV – started in 2018, does not mention long COVID
  • Prenatal Immune Activation and Maternal Mental Health as Predictors of Infant Sleep and Cognitive Development
  • Role of NLRP3 Signals in Ischemia/Reperfusion-Induced Organ Injury
  • GenoMISC: Genetic Determinants of Multisystem Inflammatory Syndrome after SARS-CoV-2 Infection in Children (MIS-C) – multisystem inflammatory syndrome is a highly dangerous, nasty syndrome that often lands children in intensive care but it occurs in the first couple of weeks after an infection; i.e. it’s not a long COVID issue.
 
I feel like it should be pointed out that the RECOVER initiative has hired at some point a communications director, which may or may not be the case. There is someone in charge of communicating what this giant secretive project is doing. Seriously.

I guess it's only for communications within the bubble. Because basically nothing is openly communicated. Seriously looks like if there's ever an investigation of this, it will find a lot of money misused as blatantly as when someone at the CDC did that.

From move fast and break things to move slow and leave the already broken things broken. Institutional mentality with startup-level oversight and accountability.
 
Jaybee00 said:
But there are funded projects that are not related to the long-term effects of Covid, apart from the MECFS subset.


The Strange – Long COVID Grants (???) – 14%
I would be shocked if Congress had these studies in mind when it funded the RECOVER project. It’s possible that some of these studies added long COVID cohorts to ongoing studies. Still, they seem like a reach.

  • Elucidating Genetic and Environmental Second Hits in Racial and Ethnic Minorities with APOL1 High-Risk Genotypes – this is a kidney disease study that was ongoing before COVID-19 and does not mention long COVID
  • Imaging Neuroglial Mechanisms of Neuropathic Pain-Opioid Interaction in HIV – started in 2018, does not mention long COVID
  • Prenatal Immune Activation and Maternal Mental Health as Predictors of Infant Sleep and Cognitive Development
  • Role of NLRP3 Signals in Ischemia/Reperfusion-Induced Organ Injury
  • GenoMISC: Genetic Determinants of Multisystem Inflammatory Syndrome after SARS-CoV-2 Infection in Children (MIS-C) – multisystem inflammatory syndrome is a highly dangerous, nasty syndrome that often lands children in intensive care but it occurs in the first couple of weeks after an infection; i.e. it’s not a long COVID issue.
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The last of those is illustrative of the point I was making - the instruction from Congress to the NIH is to commit funds to investigate: "the long-term effects of COVID", a terminology which clearly isn't limited to whatever Long Covid may include and can logically include the study of any impact of COVID on any group of affected patients.

It is true that the APOL1 study doesn't mention COVID although it's start date is given as 14/12/20, so after COVID hit, but science doesn't work on every relevant point being mentioned in every study title or description and in this case there's clear relevance to other ongoing work: COVID-19 and APOL-1 High-Risk Genotype-Associated Collapsing Glomerulonephritis

The HIV study does seem an outlier although there are comparisons to be made between HIV and COVID and a subset of PASC patients will be taking opioids for comorbidities which makes this relevant:

"The precise mechanisms by which opioids interact with the viral infection to exacerbate neuropathic pain have yet to be fully elucidated, but likely involve the synergetic dysregulation of neuro-glial interactions, including glial activation and alterations in the excitation-inhibition balance of the brain."

There's also the possibility that this HIV study is a legacy orphan of NIH carving out a whole new budgetary area at the behest Congress.

I couldn't find any documentation on the Prenatal Immune Activation study but the named researcher is working on COVID and maternal health - it would be highly significant if COVID in pregnancy has long term impacts on the child !

The objection to the Ischemia/Reperfusion-Induced Organ Injury study seems bizarre - it's an established impact of COVID infection: Liver injury in COVID-19: Detection, pathogenesis, and treatment and if the patient survives there's likely to be lifetime (i.e long term) impacts.
 
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Posts moved from the Long Covid in the media thread

Per Dr. Leonard Jason feature today from Newswise, it appears that there will be a ME/CFS cohort/comparative group included in the RECOVER Initiative.

Newswise: "Researcher Leonard A. Jason pushes discovery on long COVID, ME/CFS"

"He is a vocal advocate and serves on the diagnostics committee of the NIH’s RECOVER initiative, which is studying more than 17,000 people to learn about the long-term effects of COVID-19. Recently, Jason won NIH’s support to include an ME/CFS group as part of the work."
 
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Now the National Institutes of Health has awarded Jason $842,000 to further his research on ME/CFS with Lurie Children’s Hospital, bringing a focus on long COVID into the longitudinal study.
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The National Institute of Neurological Disorders and Stroke awarded the grant late last year to bolster Jason’s ongoing research with Dr. Ben Z. Katz, a pediatric infectious disease specialist at Lurie Children’s Hospital. Their initial study enrolled 4,500 college students to examine why ME/CFS appears in some individuals infected with Epstein-Barr virus, most commonly known for causing infectious mononucleosis. Some 50 of those patients have gone on to develop ME/CFS.

Since the outset of COVID-19, Jason and Katz have widened their efforts to explore why long COVID appears in college students who contract the SARS-CoV-2 virus. The new funding will help researchers reach back into this pool of participants and gather long COVID data.
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Worth every penny.
 
merged thread

In Nature

Long COVID exercise trials proposed by NIH raise alarm
Advocates ask the US biomedical agency to rethink the design of its RECOVER initiative, citing possible harm and funding waste.

Patients and patient advocates are calling on the US National Institutes of Health (NIH) to reconsider its decision to include exercise trials in its RECOVER initiative, which aims to study and find treatments for long COVID. They argue that a large proportion of people with long COVID have reported experiencing post-exertional malaise (PEM) — a worsening of symptoms such as fatigue, difficulty regulating body temperature and cognitive dysfunction, after even light exercise — and worry that putting certain RECOVER participants through exercise trials could cause them harm. In a petition and multiple letters, the advocates request that the NIH and affiliated physicians explain their rationale for this testing and share the trial protocols.

https://www.nature.com/articles/d41586-023-00900-w
 
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"Long COVID isn’t the first disease for which people have reported experiencing PEM. People who have myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), have long reported exacerbation of symptoms after overexertion that make their day-to-day functioning difficult. Similar to long COVID, ME/CFS often develops after a viral illness; its symptoms include PEM, cognitive impairment and joint and muscle pain."

"Although it seems counter-intuitive that exercise — normally considered an ingredient of good health — can cause harm, researchers have confirmed some of the physical effects of PEM through controlled studies. Scientists have measured people’s heart rate and oxygen intake during 2 maximal-exertion exercise tests spaced 24 hours apart. They found that those with PEM perform noticeably worse on the second day1. Meanwhile, for those without PEM — a group that included athletes, sedentary people and people with conditions such as heart failure and cystic fibrosis — results were similar, if not identical, on both days. Studies have also shown unusual patterns in gene expression2, metabolism3 and cognitive functioning4 after exertion for those with PEM."

"As researchers find out more about long COVID, it has become clear that many people with the condition meet the criteria for ME/CFS. In a study published online late last year5, researchers reported that of the 465 people with long COVID surveyed, 58% could be categorized as having ME/CFS."
 

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Text of above tweets:

Todd Davenport
@sunsopeningband

With all respect to whoever might be involved on and off this website, the NIH RECOVER program is a mess because a bunch of people are engaged who didn’t—and don’t—seem to understand prior research in (commonly) post-viral syndromes. Lack of expertise is a feature, not a bug.

What the RECOVER program seems to be quite good at doing so far is attracting investigators who understand how to apply for and spend federal research money. Science seems secondary. So, applying for and spending federal research money is what we will see done at a high level.

I sure hope I’m wrong. I’ll glad to be proven wrong. Please, dear reader, do bookmark this tweet to come back and say a hearty “I told you so” (or something far bluer of your own creation) if RECOVER yields the breakthroughs we all want to see. I will welcome it whole-heartedly.

tl;dr Just give *me* the $172 million the RECOVER program has spent so far to tell you that antivirals haven’t worked, exercise is probably a giant step in the wrong direction, and electronic health records data is nearly useless for phenotyping patients. It will be a bargain.
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