From the beginning, the RECOVER Initiative has focused on building out the massive infrastructure needed to follow and study approximately 18,000 participants. Hundreds of millions of dollars have been spent creating the main thrust of the Initiative. About a year after they began enrolling people into the study they’re about 60% of the way there.
Funding for grants for individual researchers is part of the Initiative as well, though, and presents an important opportunity for researchers outside the initiative to bring their own creative insights to long COVID. The vast majority of potential long COVID researchers, after all, are not in the RECOVER project.
Six, eight months (?) after the Initiative reported they had given out their first tranche of long COVID grants, they finally got around to releasing some information on them in August. They give us our first chance to see the fields of interest the Initiative funders are most interested in. Forty-long COVID research projects were supported to the tune of $37 million.
I used the NIH Reporter database that lists ongoing NIH-funded studies to dig into the studies and quickly hit a roadblock. Either the RECOVER Initiative is behind or doesn’t care to publish the details of its studies but of the 40 funded studies only five showed up in the NIH Reporter database and these were almost all supplements to past studies which were already in the database. That meant no detailed information on what was in the study, how big the study was, how long it would last, etc. was available. In my experience, this is quite unusual. When an ME/CFS grant is given I’ve always been able to quickly find it.
It was also rather debilitating to my analysis! NIH-funded studies tend to be much more complex and comprehensive than their titles make them out to be. I had what RECOVER provided – the titles, authors, and institutions associated with the studies. I broke the studies down into questionable long COVID studies, studies not likely to impact the ME/CFS-like subset of long COVID or long COVID, and those that could impact them.
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.
Studies Not Relevant to ME/CFS-like long COVID or ME/CFS – 24%
Long COVID can produce many different sequelae or outcomes so it was expected that some studies will not fit the ME/CFS-like Long COVID category or phenotype. Studies focusing on hospitalized patients – while they may provide some clues – are included here as well as most ME/CFS-like long COVID patients were not hospitalized and hospitalized long COVID patients may have confounding factors. A consortium grant was included in this category as well.
- Long-term Sequelae of SARS-CoV-2 Infection: Diabetes Mellitus – diabetes is not increased in ME/CFS
- Mechanisms of Long-term Taste Loss in Post-Acute Sequelae of COVID-19 – in database – taste loss is an issue in long COVID but not in ME/CFS
- Obesity, Insulin Resistance, and PASC: Persistent SARS-CoV-2 infection and Inflammation in Human Adipose Tissue – obesity is not an issue in ME/CFS
- Origins of Post-Acute Sequelae SARS-CoV-2 Infection (PASC) Lung Fibrosis – lung fibrosis is not an issue in non-hospitalized long COVID patients or in ME/CFS
- Tissue and Organ Specific Human B Cell Immunity: Supplement — Metabolic Risk Factors and Inflammation in PASC Development – another obesity and diabetes study
- Tryptophan Metabolism and Microbiome in Long-COVID Related Kidney Disease – kidney disease is a possible outcome of COVID-19 but is not increased in ME/CFS
- (PASC) in the Heart: A Cardiac Magnetic Resonance and Autopsy Study – there is no evidence of damage to the heart in ME/CFS
- Deciphering the Link Between Severe Acute Respiratory Coronavirus 2 Infection and Long-Term Neurological and Pulmonary Sequelae – appears to be on hospitalized patients
- Post-Acute Sequelae of COVID-19 (PASC) Investigators Consortium Phase 2: Researching COVID to Enhance Recovery (RECOVER) – this appears to be funding for a consortium…
The Good: ME/CFS-like Long COVID Studies 62%
About a third of the RECOVER grants, then, do not have the potential to impact the ME/CFS-like group of long COVID or ME/CFS. That leaves almost 2/3rds that might.
Immune and Viral Persistence
It was no surprise to see more immune system grants than any others. No less than four studies on autoantibodies – an area of clear interest in ME/CFS – was good to see. The ACE-2 autoantibodies study was a nice bonus given that the virus enters the cell through the ACE-2 receptor and some studies suggest that the ACE-2 receptor is messed up in ME/CFS as well. Autoantibody damage to that receptor could explain a lot in both diseases. Only one study, though, featured EBV.
Oddities – Some odd things showed up in this category. The RECOVER Initiative’s history with children is problematic. Despite the fact that few children did poorly with COVID-19, and adults make up the vast majority of ME/CFS cases, the Initiative was originally slated to follow as many children as adults. That has apparently changed. Their main page is only tracking adult enrollment. Three of the studies are studying children. One wonders, given the changing immune map in children how much they will tell us about adult onset long COVID.
Ditto with the “Immune and Neurovascular Signatures of Psychiatric Post-Acute Sequelae”. We certainly want to see studies on the blood vessels in the central nervous system but how did “psychiatric” become a focus? Scott Russo, the lead researcher has been focused on “the neural and immunological basis of neuropsychiatric disorders”. He’s received many NIH grants and is currently assessing whether “chronic stress induces neurovascular damage that weakens the blood-brain barrier and allows immune cell entry into the brain”. It’s interesting stuff but psychiatric issues are hardly central to long COVID.
There’s also the “Sex, Obesity, Immunometabolism and Viral Persistence” study. One wonders how obesity become an object of interest. This study is one of the few, though, has a detailed description – and is on much more than obesity. It will also employ the same single-cell RNA sequencing that allowed Grimson to recently highlight monocytes in ME/CFS, will focus on metabolic gene expression, and employ a recently developed mouse model. All in all, it’s an excellent study. Only one study, unfortunately, appears to be looking at viral persistence.
- Features and Functions of ACE2 Autoantibodies that Developed after SARS-CoV-2 Infection
- Characterization of Autoantibodies in PASC
- Functional Immune Responses in Children with Post-Acute Sequelae SARS-CoV-2 Infection
- Host Response to SARS-CoV-2 Infection and Its Role in PASC
- Immune and Neurovascular Signatures of Psychiatric Post-Acute Sequelae of SARS-CoV-2 Infection
- Molecular Determination of Risk for PASC by High Sensitivity Serological Analyses of Inflammatory Pathway Markers, Prior Viral Histories, and Autoantibodies
- Sequencing B Cell Repertoires to Elucidate Autoantibodies and the Role of EBV in PASC
- Sex, Obesity, Immunometabolism, and Viral Persistence in Post-Acute Sequelae of SARS-CoV-2 Infection
- Understanding Adaptive and Innate Immune Cell Dysfunction in Patients with PASC
- 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.
- Cerebral Vascular Pathology of COVID-19
- Cardiac Inflammatory and Microvascular Alterations Associated with Post-Acute Sequelae of SARS-CoV-2 Infection
- Cerebral Microvascular Integrity in Children With and Without Persistent Central Nervous System Symptomatology
- Machine Learning-Assisted Characterization of Cardiovascular Long COVID-19
- Pathophysiological Mechanisms of PASC: Inflammatory Mediators of Endothelial Dysfunction in the RECOVER Cohort
Neurological and Sleep
Four studies were focused on the nervous system – two of them on sleep – a much-neglected area in ME/CFS.
The “Neurological Sequelae Associated with Post-Acute SARS-CoV-2 Infection” study is fascinating and gives us a glimpse of how much we missed by not having the details of each study. Their preliminary data suggests that a hidden reservoir of infection is throwing the T-cells off and that ACE-2 receptor dysregulation is damaging the blood vessels in the central nervous system. They believe the blood vessel damage is throwing the sleep/wakefulness centers in the brain off.
The one small fly in the ointment with this study is that it’s focusing on older (65 years +) patients and the result may not apply to younger ones. Still, this is the kind of innovative study we would hope for from RECOVER.
- Cerebrospinal Fluid in PASC: A Window into the COVID Mind
- Viral and Immune-Mediated CNS Pathology During SARS-CoV-2 Infection
- Neurological Sequelae Associated with Post-Acute SARS-CoV-2 Infection (NEURO-PASC)
- Role of Sleep in PASC Recovery and the Development of Immunological Memory
It was good to see metabolism and viral persistence show up here. Lissa Selin will probably be happy to see the “bioenergetic T-cell fatigue (exhaustion?)” show up as she can pretty convincingly show that T-cell exhaustion could explain a lot in these diseases.
- From Big Data to Big Knowledge and AI: Connecting Multi-omics COVID-19 Cohort Data to Knowledge Graphs to Explain Pathophysiological Mechanisms of Long-COVID
- Metabolic Dysfunction, Viral Persistence and Bioenergetic T-Cell Fatigue in Post-Acute SARS-CoV
One might have liked to see more metabolic studies given the insights they’ve provided in ME/CFS, but then again metabolism might have been one area that the NIH ignored, and we got four studies that featured metabolic analyses of one sort or the other.
- Metabolic and Epigenetic Mechanisms of PASC
- Post-Acute Metabolic Sequelae of SARS-CoV-2 Infection in Nonhuman Primates – still studying primates?
- Metabolic Dysfunction, Viral Persistence and Bioenergetic T-Cell Fatigue in Post-Acute SARS-CoV (again)
- “Sex, Obesity, Immunometabolism and Viral Persistence” (again)
- Epigenetic Alterations and Phenotypes in Innate Immune Cells and Their Progenitors in PASC
- Viral and Host Genomics Influences on the Phenotypic Expression of COVID-19 Infection and Its Sequelae in Children of Varied Genetic Ancestries
Autonomic Nervous System (ANS)
A big surprise was how little funding went to autonomic nervous system studies given the prominence of ANS symptoms in long COVID.
- The Autonomic Complications of PASC Stanford study
- Improving Understanding and Diagnosis of Post-Acute Sequelae of the SARS-CoV-2 Infection
- Long COVID in the Eye (LoCEYE) Study with the RECOVER Initiative
The one major missing element was the absence of any of the exercise physiology studies which have been so revealing in ME/CFS and in long COVID as well. Because they potentially point to the core problem in these diseases – an inability to produce normal amounts of energy – the lack of exercise physiology studies is distressing. (That said, we don’t know if exercise or any other stressors are included in these studies. ) It was surprising as well, not to see any gut microbiome studies or mitochondrial studies.
Given the lack of detail provided about the studies, and the complexity of the studies the NIH typically funds, this overview missed a lot. About 15% of the studies either did not appear to meet the definition of long COVID studies or only tangentially meet them. Another quarter of the studies were on subjects not pertinent to ME/CFS or the MECFS-like subset of long COVID. Almost 2/3rds of the studies were, however.
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.
All in all, despite a few quirks it’s a strong slate of studies and should be helpful. The number of studies being funded and the amount of funding devoted to them, though, was surprisingly low. A year and a half after the $1.15 billion RECOVER Initiative started it provided all of $40 million to individual research projects. That’s just 2 1/2 times the funding that ME/CFS gets in a year and seems like a drop in the bucket for an Initiative that should be getting as much outside creative input as it can.
Did the Initiative not get many applications or is the RECOVER Initiative just not interested in funding outside researchers? (I remember something about a short application window.) I have a list of questions for the RECOVER Initiative that they have promised to answer.
Almost two years into the RECOVER Initiative it’s published one study thus far! Let’s hope the next year brings us more. It should.