Posted on by Dr. Francis Collins
It’s become increasingly clear that even healthy people with mild cases of COVID-19 can battle a constellation of symptoms that worsen over time—or which sometimes disappear only to come right back. These symptoms are part of what’s called “Long COVID Syndrome.”
Now, a new study of relatively young, healthy adult healthcare workers in Sweden adds needed information on the frequency of this Long COVID Syndrome. Published in the journal JAMA, the study found that just over 1 in 10 healthcare workers who had what at first seemed to be a relatively mild bout of COVID-19 were still coping with at least one moderate to severe symptom eight months later . Those symptoms—most commonly including loss of smell and taste, fatigue, and breathing problems—also negatively affected the work and/or personal lives of these individuals.
These latest findings come from the COVID-19 Biomarker and Immunity (COMMUNITY) study, led by Charlotte Thålin, Danderyd Hospital and Karolinska Institutet, Stockholm. The study, launched a year ago, enlisted 2,149 hospital employees to learn more about immunity to SARS-CoV-2, the coronavirus that causes COVID-19.
After collecting blood samples from participants, the researchers found that about 20 percent already had antibodies to SARS-CoV-2, evidence of a past infection. Thålin and team continued collecting blood samples every four months from all participants, who also completed questionnaires about their wellbeing.
Intrigued by recent reports in the medical literature that many people hospitalized with COVID-19 can have persistent symptoms for months after their release, the researchers decided to take a closer look in their COMMUNITY cohort. They did so last January during their third round of follow up.
This group included 323 mostly female healthcare workers, median age of 43. The researchers compared symptoms in this group following mild COVID-19 to the 1,072 mostly female healthcare workers in the study (median age 47 years) who hadn’t had COVID-19. They wanted to find out if those with mild COVID-19 coped with more and longer-lasting symptoms of feeling unwell than would be expected in an otherwise relatively healthy group of people. These symptoms included familiar things such as fatigue, muscle pain, trouble sleeping, and problems breathing.
Their findings show that 26 percent of those who had mild COVID-19 reported at least one moderate to severe symptom that lasted more than two months. That’s compared to 9 percent of participants without COVID-19. What’s more, 11 percent of the individuals with mild COVID-19 had at least one debilitating symptom that lasted for at least eight months. In the group without COVID-19, any symptoms of feeling unwell resolved relatively quickly.
The most common symptoms in the COVID-19 group were loss of taste or smell, fatigue, and breathing problems. In this group, there was no apparent increase in other symptoms that have been associated with COVID-19, including “brain fog,” problems with memory or attention, heart palpitations, or muscle and joint pain.
The researchers have noted that the Swedish healthcare workers represent a relatively young and healthy group of working individuals. Yet, many of them continued to suffer from lasting symptoms related to mild COVID-19. It’s a reminder that COVID-19 can and, in fact, is having a devastating impact on the lives and livelihoods of adults who are at low risk for developing severe and life-threatening COVID-19. If we needed one more argument for getting young people vaccinated, this is it.
At NIH, efforts have been underway for some time to identify the causes of Long COVID. In fact, a virtual workshop was held last winter with more than 1,200 participants to discuss what’s known and to fill in key gaps in our knowledge of Long COVID syndrome, which is clinically known as post-acute sequelae of COVID-19 (PASC). Recently, a workshop summary was published . As workshops and studies like this one from Sweden help to define the problem, the hope is to learn one day how to treat or prevent this terrible condition. The NIH is now investing more than $1 billion in seeking those answers.
 Symptoms and functional impairment assessed 8 Months after mild COVID-19 among health care workers. Havervall S, Rosell A, Phillipson M, Mangsbo SM, Nilsson P, Hober S, Thålin C. JAMA. 2021 Apr 7.
 Toward understanding COVID-19 recovery: National Institutes of Health workshop on postacute COVID-19. Lerner A, et al. Ann Intern Med, 2021 March 30.
COVID-19 Research (NIH)
Charlotte Thålin (Karolinska Institutet, Stockholm, Sweden)
Posted on by Dr. Francis Collins
As devastating as this pandemic has been, it’s truly inspiring to see the many innovative ways in which researchers around the world have enlisted the help of everyday citizens to beat COVID-19. An intriguing example is the COVID Symptom Study’s smartphone-based app, which already has been downloaded millions of times, mostly in the United States and United Kingdom. Analyzing data from 2.6 million app users, researchers published a paper last summer showing that self-reported symptoms can help to predict infection with SARS-CoV-2, the coronavirus that causes COVID-19 .
New work from the COVID Symptom Study now takes advantage of the smartphone app to shed more light on Long COVID Syndrome , in which people experience a constellation of symptoms long past the time that they’ve recovered from the initial stages of COVID-19 illness. Such symptoms, which can include fatigue, shortness of breath, “brain fog,” sleep disorders, fevers, gastrointestinal symptoms, anxiety, and depression, can persist for months and can range from mild to incapacitating
This latest findings, published in the journal Nature Medicine, come from a team led by Claire Steves and Tim Spector, King’s College London, and their colleagues, and that includes NIH grantee Andrew Chan, Massachusetts General Hospital, Boston, and others supported by the Massachusetts Consortium on Pathogen Readiness. The team began by looking at data recorded between March 24-Sept. 2, 2020 from about 4.2 million app users with an average age of 45, about 90 percent of whom lived in the U.K., with smaller numbers from the U.S. and Sweden.
For this particular study, the researchers decided to focused on 4,182 app users, all with confirmed COVID-19, who had consistently logged in their symptoms. Because these individuals also started using the app when they still felt physically well, the researchers could assess their COVID-19-associated symptoms over the course of the illness.
While most people who developed COVID-19 were back to normal in less than two weeks, the data suggest that one in 20 people with COVID-19 are likely to suffer symptoms of Long COVID that persist for eight weeks or more. About one in 50 people continued to have symptoms for 12 weeks or more. That suggests Long COVID could potentially affect many hundreds of thousands of people in the U.K. alone and millions more worldwide.
The team found that the individuals most likely to develop Long COVID were older people, women, and especially those who experienced five or more symptoms. The nature and order of symptoms, which included fatigue, headache, shortness of breath, and loss of smell, didn’t matter. People with asthma also were more likely to develop long-lasting symptoms, although the study found no clear links to any other pre-existing health conditions.
Using this information, the researchers developed a model to predict which individuals were most likely to develop Long COVID. Remarkably, this simple algorithm—based on age, gender, and number of early symptoms–accurately predicted almost 70 percent of cases of Long COVID. It was also about 70 percent effective in avoiding false alarms.
The team also validated the algorithm’s predictive ability in data from an independent group of 2,472 people with confirmed COVID-19 and a range of symptoms. In this group, having more than five symptoms within the first week also proved to be the strongest predictor of Long COVID. And, again, the model worked quite well in identifying those most likely to develop Long COVID.
These findings come as yet another important reminder of the profound impact of the COVID-19 pandemic on public health. This includes not only people who are hospitalized with severe COVID-19 but, all too often, those who get through the initial period of infection relatively unscathed.
Recently, NIH announced a $1.15 billion investment to identify the causes of Long COVID, to develop ways of treating individuals who don’t fully recover, and, ultimately, to prevent the disorder. We’ve been working diligently in recent weeks to identify the most pressing questions and areas of greatest opportunity to address this growing public health threat. As a first step, NIH is funding an effort to track the recovery paths of at least 40,000 adults and children infected with SARS-CoV-2, to learn more about who develops long-term effects and who doesn’t. If you’d like to find a way to pitch in and help, getting involved in the COVID Symptom Study is as easy as downloading the app.
 Real-time tracking of self-reported symptoms to predict potential COVID-19. Menni C, Valdes AM, Freidin MB, Sudre CH, Nguyen LH, Drew DA, Ganesh S, Varsavsky T, Cardoso MJ, El-Sayed Moustafa JS, Visconti A, Hysi P, Bowyer RCE, Mangino M, Falchi M, Wolf J, Ourselin S, Chan AT, Steves CJ, Spector TD. Nat Med. 2020 Jul;26(7):1037-1040. doi: 10.1038/s41591-020-0916-2. Epub 2020 May 11.
 Attributes and predictors of long COVID. Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, Pujol JC, Klaser K, Antonelli M, Canas LS, Molteni E, Modat M, Jorge Cardoso M, May A, Ganesh S, Davies R, Nguyen LH, Drew DA, Astley CM, Joshi AD, Merino J, Tsereteli N, Fall T, Gomez MF, Duncan EL, Menni C, Williams FMK, Franks PW, Chan AT, Wolf J, Ourselin S, Spector T, Steves CJ. Nat Med. 2021 Mar 10.
NIH launches new initiative to study to “Long COVID”. 2021 Feb 23. (NIH)
COVID-19 Research (NIH)
Claire Steves (King’s College London, United Kingdom)
Tim Spector (King’s College London)
Andrew Chan (Massachusetts General Hospital, Boston)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases
Posted on by Dr. Francis Collins
More than 400,000 Americans have now lost their lives to COVID-19. But thousands of others who’ve gotten sick and survived COVID-19 are finding that a full recovery can be surprisingly elusive. Weeks and months after seemingly recovering from even mild cases of COVID-19, many battle a wide range of health problems.
Indeed, new results from the largest global study of this emerging “Long COVID syndrome” highlight just how real and pressing this public health concern really is. The study, reported recently as a pre-print on medRxiv, is based on survey results from more than 3,700 self-described COVID “Long Haulers” in 56 countries . They show nearly half couldn’t work full time six months after unexpectedly developing prolonged symptoms of COVID-19. A small percentage of respondents, thankfully, seemed to have bounced back from brief bouts of Long COVID, though time will tell whether they have fully recovered.
These findings are the second installment from the online Body Politic COVID-19 Support Group and its Patient-Led Research for COVID-19, which consists of citizen scientists with a wide range of expertise in the arts and sciences who are struggling with the prolonged effects of COVID-19 themselves. In an earlier survey, this group provided a first-draft description of Long COVID syndrome, based on the self-reported experiences of 640 respondents.
In the new survey-based study led by Athena Akrami, with Patient-Led Research for COVID-19 and University College London, England, the goal was to characterize the experiences of many more people with Long COVID syndrome. They now define the syndrome as a collection of symptoms lasting for more than 28 days.
This second survey emphasizes the course and severity of more than 200 symptoms over time, including those affecting the heart, lungs, gastrointestinal system, muscles, and joints. It took a particularly in-depth look at neurological and neuropsychiatric symptoms, along with the ability of COVID-19 survivors to return to work and participate in other aspects of everyday life.
The 3,762 individuals who responded to the survey were predominately white females, between the ages of 30 and 60, who lived in the United States. As in the previous survey, the study included adults with symptoms consistent with COVID-19, whether or not the infection had been confirmed by a viral or antibody test. That is a potential weakness of the study, as some of these individuals may have had some other inciting illness. But many of the study’s participants developed symptoms early on in the pandemic, when testing was much more limited than it is now.
More than half never sought hospital care. Only 8 percent said that they’d been admitted to the hospital for COVID-19. And yet, 2,464 respondents reported COVID-19 symptoms lasting six months or longer. Most of the remaining respondents also continued to have symptoms, although they had not yet reached the six-month mark.
Among the most common symptoms were fatigue, worsening of symptoms after physical or mental activity, shortness of breath, trouble sleeping, and “brain fog,” or difficulty thinking clearly. The majority—88 percent—said they coped with some form of cognitive dysfunction or memory loss that to varying degrees affected their everyday lives. That includes the ability to make decisions, have conversations, follow instructions, and drive.
Those who had prolonged symptoms of COVID-19 for more than six months reported contending with about 14 symptoms on average. Most also reported that they’d had a relapse of symptoms, seemingly triggered by exercise, mental activity, or just everyday stress. When surveyed, nearly half of respondents said they’d had to reduce their hours at work due to the severity of their symptoms. Another 22 percent weren’t working at all due to their Long COVID.
The findings show that—even in those people who don’t require hospitalization for severe COVID-19—the condition’s prolonged symptoms are having a major impact on lives and livelihoods, both here and around the world. While the number of people affected isn’t yet known, if even a small proportion of the vast numbers of people infected with COVID-19 develop Long COVID syndrome, it represents a significant public health concern.
Another recent study from China further documents the tendency of COVID-19-related symptoms to linger past the usual recovery time for a respiratory virus . The study, published in Lancet, showed that six months after the onset of illness, more than 75 percent of people hospitalized with COVID-19 in Wuhan between January and May 2020 continued to report at least one symptom. Fatigue, muscle weakness, sleep difficulties, anxiety, and depression all were common. More than half of individuals also had significant persistent lung abnormalities, which were more common in those who’d been more severely ill.
It’s essential for us to learn all we can about how SARS-CoV-2, which is the coronavirus that causes COVID-19, leads to such widespread symptoms. It’s also essential that we develop ways to better treat or prevent these symptoms. The NIH held a workshop last month to summarize what is known and fill in key gaps in our knowledge about Long COVID syndrome, which is clinically known as post-acute sequelae of COVID-19 (PASC). In December, Congress authorized funding for continued research on PASC, including an appropriation of funds for NIH to support continued study of these prolonged health consequences.
As these efforts and others proceed in the coming months, the hope is that we’ll gain much more insight and get some answers soon. And, if you’ve had or are currently experiencing symptoms of COVID-19, there’s still time to share your data by participating in the Patient-Led Research for COVID-19’s second survey.
 Characterizing Long COVID in an international cohort: 7 months of symptoms and their impact. David HE et al. Medrxiv. 27 December 27 2020.
 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Huang C, Huang L, et al. Lancet. 2021 Jan 16;397(10270):220-232.
COVID-19 Research (NIH)
Posted on by Dr. Francis Collins
While primarily a respiratory disease, COVID-19 can also lead to neurological problems. The first of these symptoms might be the loss of smell and taste, while some people also may later battle headaches, debilitating fatigue, and trouble thinking clearly, sometimes referred to as “brain fog.” All of these symptoms have researchers wondering how exactly the coronavirus that causes COVID-19, SARS-CoV-2, affects the human brain.
In search of clues, researchers at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) have now conducted the first in-depth examinations of human brain tissue samples from people who died after contracting COVID-19. Their findings, published in the New England Journal of Medicine, suggest that COVID-19’s many neurological symptoms are likely explained by the body’s widespread inflammatory response to infection and associated blood vessel injury—not by infection of the brain tissue itself .
The NIH team, led by Avindra Nath, used a high-powered magnetic resonance imaging (MRI) scanner (up to 10 times as sensitive as a typical MRI) to examine postmortem brain tissue from 19 patients. They ranged in age from 5 to 73, and some had preexisting conditions, such as diabetes, obesity, and cardiovascular disease.
The team focused on the brain’s olfactory bulb that controls our ability to smell and the brainstem, which regulates breathing and heart rate. Based on earlier evidence, both areas are thought to be highly susceptible to COVID-19.
Indeed, the MRI images revealed in both regions an unusual number of bright spots, a sign of inflammation. They also showed dark spots, which indicate bleeding. A closer look at the bright spots showed that tiny blood vessels in those areas were thinner than normal and, in some cases, leaked blood proteins into the brain. This leakage appeared to trigger an immune reaction that included T cells from the blood and the brain’s scavenging microglia. The dark spots showed a different pattern, with leaky vessels and clots but no evidence of an immune reaction.
While those findings are certainly interesting, perhaps equally noteworthy is what Nath and colleagues didn’t see in those samples. They could find no evidence in the brain tissue samples that SARS-CoV-2 had invaded the brain tissue. In fact, several methods to detect genetic material or proteins from the virus all turned up empty.
The findings are especially intriguing because there has been some suggestion based on studies in mice that SARS-CoV-2 might cross the blood-brain barrier and invade the brain. Indeed, a recent report by NIH-funded researchers in Nature Neuroscience showed that the viral spike protein, when injected into mice, readily entered the brain along with many other organs .
Another recent report in the Journal of Experimental Medicine, which used mouse and human brain tissue, suggests that SARS-CoV-2 may indeed directly infect the central nervous system, including the brain . In autopsies of three people who died from complications of COVID-19, the NIH-supported researchers detected signs of SARS-CoV-2 in neurons in the brain’s cerebral cortex. This work was done using the microscopy-based technique of immunohistochemistry, which uses antibodies to bind to a target, in this case, the virus’s spike protein. Also last month, in a study published in the journal Neurobiology of Disease, another NIH-supported team demonstrated in a series of experiments in cell culture that the SARS-CoV-2 spike protein could cross a 3D model of the blood-brain barrier and infect the endothelial cells that line blood vessels in the brain .
Clearly, more research is needed, and NIH’s National Institute of Neurological Disorders and Stroke has just launched the COVID-19 Neuro Databank/Biobank (NeuroCOVID) to collect more clinical information, primarily about COVID-19-related neurological symptoms, complications, and outcomes. Meanwhile, Nath and colleagues continue to explore how COVID-19 affects the brain and triggers the neurological symptoms often seen in people with COVID-19. As we learn more about the many ways COVID-19 wreaks havoc on the body, understanding the neurological symptoms will be critical in helping people, including the so-called Long Haulers bounce back from this terrible viral infection.
 Microvascular Injury in the Brains of Patients with Covid-19. Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. N Engl J Med. 2020 Dec 30.
 The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. Nat Neurosci. 2020 Dec 16.
 Neuroinvasion of SARS-CoV-2 in human and mouse brain. Song E, Zhang C, Israelow B, et al. J Exp Med (2021) 218 (3): e20202135.
 The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, Bullock TA, McGary HM, Khan JA, Razmpour R, Hale JF, Galie PA, Potula R, Andrews AM, Ramirez SH. Neurobiol Dis. 2020 Dec;146:105131.
COVID-19 Research (NIH)
Avindra Nath (National Institute of Neurological Disorders and Stroke/NIH)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Aging; National Institute of General Medical Sciences; National Cancer Institute; National Institute of Mental Health
Posted on by Dr. Francis Collins
The past several months have shown that most people hospitalized with COVID-19 will get better. As inspiring as it is to see these patients breathe on their own and converse with their loved ones again, we are learning that many will leave the hospital still quite ill and in need of further care. But little has been published to offer a detailed demographic picture of those being discharged from our nation’s hospitals and the types of community-based care and monitoring that will be needed to keep them on the road to recovery.
A recent study in the journal EClinicalMedicine helps to fill in those gaps by chronicling the early COVID-19 experience of three prominent hospitals in the Boston area: Massachusetts General Hospital, Brigham and Women’s Hospital, and Newton-Wellesley Hospital. These data were reported from a patient registry of 247 middle-aged and older COVID-19 patients. The patients were admitted over three weeks last March into one of these hospitals, which are part of New England’s largest integrated health network.
The data confirm numerous previous reports that COVID-19 disproportionately affects people of color. The researchers, led by Jason H. Wasfy and Cian P. McCarthy, Massachusetts General Hospital and Harvard Medical School, Boston, found a large number of their patients were Hispanic (30 percent) or Black (10 percent). Wasfy said these numbers could be driven by many factors, including a low income, more family members living in one home, greater difficulty accessing healthcare, presence of chronic illness (health disparities), and serving as essential workers during the pandemic.
The researchers also tracked the patients after discharge for about 80 days. About a third of patients left the hospital for a post-acute care facility to continue their rehabilitation. After discharge, many required supplemental oxygen (15 percent), tube feeding (9 percent), or treatment with medications including antipsychotics and prescription painkillers (16 percent). About 10 percent were readmitted to the hospital within weeks or months of their initial discharge.
Wasfy and colleagues also found:
· Many patients undergoing treatment were enrolled in Medicaid (20 percent) or both Medicaid and Medicare (12 percent).
· A substantial number also were retired (36 percent) or unemployed (8.5 percent), highlighting the role of non-occupational spread. Many others worked in the hospitality industry, healthcare, or public transportation.
· A large proportion (42 percent) of hospitalized patients required intensive care. The good news is that most of them (86 percent) ultimately recovered enough to be discharged from the hospital. Tragically, 14 percent—34 of 247 people—died in the hospital.
These findings represent hospitals in just one notable American city hard hit early in the pandemic. But they spotlight the importance of public health efforts to prevent COVID-19 among the most vulnerable and reduce its most devastating social impacts. These are critical points, and NIH has recently begun supporting community engagement research efforts in areas hardest hit by COVID-19. With this support and access to needed post-discharge care, we aim to help more COVID survivors stay on the road to a full recovery.
 Early clinical and sociodemographic experience with patients hospitalized with COVID-19 at a large American healthcare system. McCarthy CP et al. EClinicalMedicine. August 19, 2020.
Coronavirus (COVID-19) (NIH)
Massachusetts General Hospital (Boston)
Brigham and Women’s Hospital (Boston)
Newton-Wellesley Hospital (Newton, MA)
Jason Wasfy (Massachusetts General Hospital)