chronic disease
Understanding Long-Term COVID-19 Symptoms and Enhancing Recovery
Posted on by Walter J. Koroshetz, M.D., National Institute of Neurological Disorders and Stroke
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.
The initiative studies core questions such as why COVID-19 infections can have lingering effects, why new symptoms may develop, and what is the impact of SARS-CoV-2, the virus that causes COVID-19, on other diseases and conditions? Answering these fundamental questions will help to determine the underlying biologic basis of Long COVID. The answers will also help to tell us who is at risk for Long COVID and identify therapies to prevent or treat the condition.
The RECOVER initiative’s wide scope of research is also unprecedented. It is needed because Long COVID is so complex, and history indicates that similar post infectious conditions have defied definitive explanation or effective treatment. Indeed, those experiencing Long COVID report varying symptoms, making it highly unlikely that a single therapy will work for everyone, underscoring the need to pursue multiple therapeutic strategies.
To understand Long COVID fully, hundreds of RECOVER investigators are recruiting more than 17,000 adults (including pregnant people) and more than 18,000 children to take part in cohort studies. Hundreds of enrolling sites have been set up across the country. An autopsy research cohort will also provide further insight into how COVID-19 affects the body’s organs and tissues.
In addition, researchers will analyze electronic health records from millions of people to understand how Long COVID and its symptoms change over time. The RECOVER initiative is also utilizing consistent research protocols across all the study sites. The protocols have been carefully developed with input from patients and advocates, and they are designed to allow for consistent data collection, improve data sharing, and help to accelerate the pace of research.
From the very beginning, people suffering from Long COVID have been our partners in RECOVER. Patients and advocates have contributed important perspectives and provided valuable input into the master protocols and research plans.
Now, with RECOVER underway, individuals with Long COVID, their caregivers, and community members continue to serve a critical role in the Initiative. The National Community Engagement Group (NCEG) has been established to make certain that RECOVER meets the needs of all people affected by Long COVID. The RECOVER Patient and Community Engagement Strategy outlines all the approaches that RECOVER is using to engage with and gather input from individuals impacted by Long COVID.
The NIH recently made more than 40 awards to improve understanding of the underlying biology and pathology of Long COVID. There have already been several important findings published by RECOVER scientists.
For example, in a recent study published in the journal Lancet Digital Health, RECOVER investigators used machine learning to comb through electronic health records to look for signals that may predict whether someone has Long COVID [1]. As new findings, tools, and technologies continue to emerge that help advance our knowledge of the condition, the RECOVER Research Review (R3) Seminar Series will provide a forum for researchers and our partners with up-to-date information about Long COVID research.
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.
Unlike other post-viral conditions, people who experience Long COVID were all infected by the same virus—albeit different variants—at a similar point in time. This creates a unique opportunity for RECOVER researchers to study post-viral conditions in real-time.
The opportunity enables scientists to study many people simultaneously while they are still infected to monitor their progress and recovery, and to try to understand why some individuals develop ongoing symptoms. A better understanding of the transition from acute to chronic disease may offer an opportunity to intervene, identify who is at risk of the transition, and develop therapies for people who experience symptoms long after the acute infection has resolved.
The RECOVER initiative will soon announce clinical trials, leveraging data from clinicians and patients in which symptom clusters were identified and can be targeted by various interventions. These trials will investigate therapies that are indicated for other non-COVID conditions and novel treatments for Long COVID.
Through extensive collaboration across the multiple NIH institutes and offices that contribute to the RECOVER effort, our hope is critical answers will emerge soon. These answers will help us to recognize the full range of outcomes and needs resulting from PASC and, most important, enable many people to make a full recovery from COVID-19. We are indebted to the over 10,000 subjects who have already enrolled in RECOVER. Their contributions and the hard work of the RECOVER investigators offer hope for the future to the millions still suffering from the pandemic.
Reference:
[1] Identifying who has long COVID in the USA: a machine learning approach using N3C data. Pfaff ER, Girvin AT, Bennett TD, Bhatia A, Brooks IM, Deer RR, Dekermanjian JP, Jolley SE, Kahn MG, Kostka K, McMurry JA, Moffitt R, Walden A, Chute CG, Haendel MA; N3C Consortium. Lancet Digit Health. 2022 Jul;4(7):e532-e541.
Links:
COVID-19 Research (NIH)
Long COVID (NIH)
RECOVER: Researching COVID to Enhance Recovery (NIH)
“NIH builds large nationwide study population of tens of thousands to support research on long-term effects of COVID-19,” NIH News Release, September 15, 2021.
Director’s Messages (National Institute of Neurological Disorders and Stroke/NIH)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 18th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Biology of Aging Study Shows Why Curbing Calories Counts
Posted on by Richard J. Hodes, M.D., National Institute on Aging
The NIH’s National Institute on Aging (NIA) broadly invests in research to find ways to help people live longer and healthier. As people age, they are more likely to have multiple chronic diseases, and NIA-supported research studies reflect a strong focus on geroscience. This advancing area of science seeks to understand the mechanisms that make aging a major risk factor and driver of common chronic conditions and diseases of older people.
More than 85 years ago, researchers at Cornell University, Ithaca, NY, observed that some lab rodents lived longer when fed a lower calorie diet that otherwise had the appropriate nutrients [1]. Since then, many scientists have studied calorie restriction to shed light on the various biological mechanisms that may explain its benefits and perhaps discover a way to extend healthy years of life, known as our healthspan.
Although there have been many studies of calorie restriction since the Cornell findings, the NIA-supported clinical trial CALERIE, which stands for Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy, provided critical data on the impact of this intervention in people. Completed in 2012, CALERIE was the first carefully controlled study to test whether study participants undergoing moderate calorie restriction would display any of the benefits observed in animal studies.
Volunteers for the CALERIE study were healthy, non-obese adults ages 25 to 45. People in one group were randomly assigned to continue their customary dietary choices, and those in the second group were trained by an expert team of psychologists and dietitians to restrict calories through specific strategies, such as eating smaller servings of food.
In addition to demonstrating that people could sustain moderate calorie restriction for two years, the CALERIE study also showed that this intervention could diminish risk factors for age-related cardiovascular and metabolic diseases [2]. The CALERIE investigators also made their data and biological samples available for other research teams to study further.
Recently, a team led by Vishwa Dixit, Yale University, New Haven, CT, examined CALERIE data to investigate the effects of calorie restriction on immune function. The findings, published in the journal Science, suggest that calorie restriction may improve immune function and reduce chronic inflammation [3,4].
As people age, the size of the thymus, which is part of the immune system, tends to become smaller. As this organ shrinks, its output of T cells declines, which hampers the ability of the immune system to combat infectious diseases. This deficiency of T cells is one of the reasons people over age 40 are at increased susceptibility for a range of diseases.
Dixit’s team noted that MRI scans showed the thymus volume increased among people who reduced their calories for the two-year CALERIE study but was not significantly different in the control group. The increase in thymus size in the group restricting calories was accompanied by an increase in indicators of new T cell production.
Next, the team analyzed immune system effects in belly fat samples from people in the CALERIE study. The team discovered that the PLA2G7 gene—which codes for a protein involved in fat metabolism that is made by immune cells such as T cells—was suppressed after calorie restriction, with evidence that the suppression occurred in immune cells present in fat. They hypothesized that the PLA2G7 gene could have played a role in the improved thymus function resulting from calorie restriction.
To test this hypothesis, the team suppressed the Pla2g7 gene in lab mice. When these mice were two years old, which is equivalent to a human age of about 70, the thymus had not decreased in volume. In addition, the mice had decreased fat mass and lower levels of certain inflammation-promoting substances. These findings suggest that mice without the Pla2g7 gene might have been protected from age-related chronic inflammation, which has been linked to many conditions of old age.
Taken together, the findings extend our understanding of the power of calorie restriction and suggest that it might also improve immune function and reduce chronic inflammation in people. The results also indicate interventions that influence PLA2G7 gene function might have favorable health effects. Additional research is still needed to assess the health effects and to determine whether calorie restriction extends lifespan or healthspan in humans. The NIA is funding more studies to determine the benefits and risks of calorie restriction, as well as the mechanisms that account for its effects.
References:
[1] The effect of retarded growth upon the length of life span and upon the ultimate body size. McCay CM, Crowell MF, Maynard LA. J. Nutr. 1935 July 10(1): 63–79.
[2] A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB; CALERIE Study Group. J Gerontol A Biol Sci Med Sci. 2015 Sep;70(9):1097-104.
[3] Caloric restriction in humans reveals immunometabolic regulators of health span. Spadaro O, Youm Y, Shchukina I, Ryu S, Sidorov S, Ravussin A, Nguyen K, Aladyeva E, Predeus AN, Smith SR, Ravussin E, Galban C, Artyomov MN, Dixit VD. Science. 2022 Feb 11;375(6581):671-677.
[4] Caloric restriction has a new player. Rhoads TW and Anderson RM. Science. 2022 Feb 11;375(6581):620-621.
Links:
Dietary Restriction (National Institute on Aging, NIH)
What Do We Know About Healthy Aging? (NIA)
Calorie Restriction and Fasting Diets: What Do We Know? (NIA)
Live Long in Good Health: Could Calorie Restriction Mimetics Hold the Key? (NIA)
Geroscience: The Intersection of Basic Aging Biology, Chronic Disease, and Health (NIA)
Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) (NIA)
CALERIE Intensive Intervention Database (NIA)
Research Highlights (NIA)
Vishwa Deep Dixit (Yale University, New Haven, CT)
CALERIE Research Network (Duke University, Durham, N.C.)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the cool science that they support and conduct. This is the fourth in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]
Can Childhood Stress Affect the Immune System?
Posted on by Dr. Francis Collins
Katie Ehrlich
Credit: Alan Flurry, University of Georgia, Athens
Whether it’s growing up in gut-wrenching poverty, dealing with dysfunctional family dynamics, or coping with persistent bullying in school, extreme adversity can shatter a child’s sense of emotional well-being. But does it also place kids at higher of developing heart disease, diabetes, and other chronic health conditions as adults?
Katherine Ehrlich, a researcher at University of Georgia, Athens, wants to take a closer look at this question. She recently received a 2018 NIH Director’s New Innovator Award to study whether acute or chronic psychosocial stress during childhood might sensitize the body’s immune system to behave in ways that damage health, possibly over the course of a lifetime.
Moving Toward Answers in ME/CFS
Posted on by Dr. Walter Koroshetz and Dr. Francis Collins
Thinkstock/Katarzyna Bialasiewicz
Updated September 27, 2017: The National Institutes of Health (NIH) will award four grants to establish a coordinated scientific research effort on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The total cost of the projects for fiscal year 2017 will be over $7 million, with support from multiple NIH Institutes and Centers that are part of the Trans-NIH ME/CFS Working Group.
The grants will support the creation of a consortium made up of three Collaborative Research Centers (CRC) and a Data Management Coordinating Center (DMCC). The CRCs will each conduct independent research but will also collaborate on several projects, forming a network to help advance knowledge on ME/CFS. The data will be managed by the DMCC and will be shared among researchers within the CRCs and more broadly with the research community.
Imagine going to work or school every day, working out at the gym, spending time with family and friends—basically, living your life in a full and vigorous way. Then one day, you wake up, feeling sick. A bad cold maybe, or perhaps the flu. A few days pass, and you think it should be over—but it’s not, you still feel achy and exhausted. Now imagine that you never get better— plagued by unrelenting fatigue not relieved by sleep. Any exertion just makes you worse. You are forced to leave your job or school and are unable to participate in any of your favorite activities; some days you can’t even get out of bed. The worst part is that your doctors don’t know what is wrong and nothing seems to help.
Unfortunately, this is not fiction, but reality for at least a million Americans—who suffer from a condition that carries the unwieldy name of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a perplexing disease that biomedical research desperately needs to unravel [1]. Very little is currently known about what causes ME/CFS or its biological basis [2]. Among the many possibilities that need to be explored are problems in cellular metabolism and changes in the immune system.
Big Data Study Reveals Possible Subtypes of Type 2 Diabetes
Posted on by Dr. Francis Collins
Caption: Computational model showing study participants with type 2 diabetes grouped into three subtypes, based on similarities in data contained in their electronic health records. Such information included age, gender (red/orange/yellow indicates females; blue/green, males), health history, and a range of routine laboratory and medical tests.
Credit: Dudley Lab, Icahn School of Medicine at Mount Sinai, New York
In recent years, there’s been a lot of talk about how “Big Data” stands to revolutionize biomedical research. Indeed, we’ve already gained many new insights into health and disease thanks to the power of new technologies to generate astonishing amounts of molecular data—DNA sequences, epigenetic marks, and metabolic signatures, to name a few. But what’s often overlooked is the value of combining all that with a more mundane type of Big Data: the vast trove of clinical information contained in electronic health records (EHRs).
In a recent study in Science Translational Medicine [1], NIH-funded researchers demonstrated the tremendous potential of using EHRs, combined with genome-wide analysis, to learn more about a common, chronic disease—type 2 diabetes. Sifting through the EHR and genomic data of more than 11,000 volunteers, the researchers uncovered what appear to be three distinct subtypes of type 2 diabetes. Not only does this work have implications for efforts to reduce this leading cause of death and disability, it provides a sneak peek at the kind of discoveries that will be made possible by the new Precision Medicine Initiative’s national research cohort, which will enroll 1 million or more volunteers who agree to share their EHRs and genomic information.
