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Trying to Make Sense of Long COVID Syndrome

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Credit: NIH

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 [1]. 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 [2]. 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.

References:

[1] Characterizing Long COVID in an international cohort: 7 months of symptoms and their impact. David HE et al. Medrxiv. 27 December 27 2020.

[2] 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.

Links:

COVID-19 Research (NIH)

Akrami Lab (Sainsbury Wellcome Center, University College London, England)

Patient-led Research for COVID-19

Video: Workshop on Post-Acute Sequelae of COVID-19 (NIH)


A Close-up of COVID-19 in Lung Cells

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SARS-CoV-2 infected lung cells
Credit: Ehre Lab, UNC School of Medicine

If you or a loved one have come down with SARS-CoV-2, the coronavirus responsible for COVID-19, you know it often takes hold in the respiratory system. This image offers a striking example of exactly what happens to cells in the human airway when this coronavirus infects them.

This colorized scanning electron microscope (SEM) image shows SARS-CoV-2-infected human lung cells (purple) covered in hair-like cilia (blue). Those cilia line the inner surface of the airways and help to clear mucus (yellow-green) containing dust and other debris from the lungs. Emerging from the surface of those infected airway cells are many thousands of coronavirus particles (red).

This dramatic image, published recently in the New England Journal of Medicine, comes from the lab of pediatric pulmonologist Camille Ehre, University of North Carolina at Chapel Hill. Ehre and team study mucus and how its properties change in cystic fibrosis, chronic obstructive pulmonary disease (COPD), and various other conditions that affect the lungs. These days, they’re also focusing their attention on SARS-CoV-2 and potentially new ways to block viral entry into cells of the human airway.

As part of that effort, she and her colleagues captured this snapshot of SARS-CoV-2 viruses exiting from lung cells in a lab dish. They first cultured cells from the lining of a human airway, then inoculated them with the virus. Ninety-six hours later, this is what they saw in greyscale. The vivid colors were added later by UNC medical student Cameron Morrison.

The image illustrates the astoundingly large number of viral particles that can be produced and released from infected human cells. Ehre notes that in a lab dish containing about a million human cells, they’ve witnessed the virus explode from about 1,000 particles to about 10 million in just a couple of days.

The dramatic increase in viral particles helps to explain how COVID-19 spreads so easily from the lungs to other parts of the body and—all too often—on to other individuals, especially in crowded, indoor places where people aren’t able to keep their distance. Hopefully, images like this one will help to inspire more of us this winter to avoid the crowds (especially indoors), wear masks, and wash our hands frequently.

Reference:

[1] SARS-CoV-2 infection of airway cells. Ehre C. NEJM. 2020 Sep 3;383(10):969.

Links:

Coronavirus (COVID-19) (NIH)

Camille Ehre (University of North Carolina, Chapel Hill)


Mini-Lungs in a Lab Dish Mimic Early COVID-19 Infection

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Credit: Arvind Konkimalla, Tata Lab, Duke University, Durham, NC

Researchers have become skilled at growing an array of miniature human organs in the lab. Such lab-grown “organoids” have been put to work to better understand diabetes, fatty liver disease, color vision, and much more. Now, NIH-funded researchers have applied this remarkable lab tool to produce mini-lungs to study SARS-CoV-2, the coronavirus that causes COVID-19.

The intriguing bubble-like structures (red/clear) in the mini-lung pictured above represent developing alveoli, the tiny air sacs in our lungs, where COVID-19 infections often begin. In this organoid, the air sacs consist of many thousands of cells, all of which arose from a single adult stem cell isolated from tissues found deep within healthy human lungs. When carefully nurtured in lab dishes, those so-called alveolar epithelial type-2 cells (AT2s) begin to multiply. As they grow, they spontaneously assemble into structures that closely resemble alveoli.

A team led by Purushothama Rao Tata, Duke University School of Medicine, Durham, NC, developed these mini-lungs in a quest to understand how adult stem cells help to regenerate damaged tissue in the deepest recesses of the lungs, where SARS-CoV-2 attacks. In earlier studies, the researchers had shown it was possible for these cells to produce miniature alveoli. But there was a problem: the “soup” they used to nurture the growing cells included ingredients that weren’t well defined, making it hard to characterize the experiments fully.

In the study, now reported in Cell Stem Cell, the researchers found a way to simplify and define that brew. For the first time, they could produce mini-lungs consisting only of human lung cells. By growing them in large numbers in the lab, they can now learn more about SARS-CoV-2 infection and look for new ways to prevent or treat it.

Tata and his collaborators at the University of North Carolina, Chapel Hill, have already confirmed that SARS-CoV-2 infects the mini-lungs via the critical ACE2 receptor, just as the virus is known to do in the lungs of an infected person.

Interestingly, the cells also produce cytokines, inflammatory molecules that have been tied to tissue damage. The findings suggest the cytokine signals may come from the lungs themselves, even before immune cells arrive on the scene.

The heavily infected lung cells eventually self-destruct and die. In an unexpected turn of events, they even induce cell death in some neighboring healthy cells that are not infected. The relevance of the studies to the clinic was boosted by the finding that the gene activity patterns in the mini-lungs are a close match to those found in samples taken from six patients with severe COVID-19.

Now that he’s got the recipe down, Tata is busy making organoids and helping to model COVID-19 infections, with the hope of identifying and testing promising new treatments. It’s clear these mini-lungs are breathing some added life into the basic study of COVID-19.

Reference:

[1] Human lung stem cell-based alveolospheres provide insights into SARS-CoV-2-mediated interferon responses and pneumocyte dysfunction. Katsura H, Sontake V, Tata A, Kobayashi Y, Edwards CE, Heaton BE, Konkimalla A, Asakura T, Mikami Y, Fritch EJ, Lee PJ, Heaton NS, Boucher RC, Randell SH, Baric RS, Tata PR. Cell Stem Cell. 2020 Oct 21:S1934-5909(20)30499-9.

Links:

Coronavirus (COVID-19) (NIH)

Tata Lab (Duke University School of Medicine, Durham, NC)

NIH Support: National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Institute of Diabetes and Digestive and Kidney Diseases


Months After Recovery, COVID-19 Survivors Often Have Persistent Lung Trouble

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Lung function test
Caption: Testing breathing capacity with a spirometer. Credit: iStock/Koldunov

The pandemic has already claimed far too many lives in the United States and around the world. Fortunately, as doctors have gained more experience in treating coronavirus disease 2019 (COVID-19), more people who’ve been hospitalized eventually will recover. This raises an important question: what does recovery look like for them?

Because COVID-19 is still a new condition, there aren’t a lot of data out there yet to answer that question. But a recent study of 55 people recovering from COVID-19 in China offers some early insight into the recovery of lung function [1]. The results make clear that—even in those with a mild-to-moderate infection—the effects of COVID-19 can persist in the lungs for months. In fact, three months after leaving the hospital about 70 percent of those in the study continued to have abnormal lung scans, an indication that the lungs are still damaged and trying to heal.

The findings in EClinicalMedicine come from a team in Henan Province, China, led by Aiguo Xu, The First Affiliated Hospital of Zhengzhou University; Yanfeng Gao, Zhengzhou University; and Hong Luo, Guangshan People’s Hospital. They’d heard about reports of lung abnormalities in patients discharged from the hospital. But it wasn’t clear how long those problems stuck around.

To find out, the researchers enrolled 55 men and women who’d been admitted to the hospital with COVID-19 three months earlier. Some of the participants, whose average age was 48, had other health conditions, such as diabetes or heart disease. But none had any pre-existing lung problems.

Most of the patients had mild or moderate respiratory illness while hospitalized. Only four of the 55 had been classified as severely ill. Fourteen patients required supplemental oxygen while in the hospital, but none needed mechanical ventilation.

Three months after discharge from the hospital, all of the patients were able to return to work. But they continued to have lingering symptoms of COVID-19, including shortness of breath, cough, gastrointestinal problems, headache, or fatigue.

Evidence of this continued trouble also showed up in their lungs. Thirty-nine of the study’s participants had an abnormal result in their computed tomography (CT) lung scan, which creates cross-sectional images of the lungs. Fourteen individuals (1 in 4) also showed reduced lung function in breathing tests.

Interestingly, the researchers found that those who went on to have more lasting lung problems also had elevated levels of D-dimer, a protein fragment that arises when a blood clot dissolves. They suggest that a D-dimer test might help to identify those with COVID-19 who would benefit from pulmonary rehabilitation to rebuild their lung function, even in the absence of severe respiratory symptoms.

This finding also points to the way in which the SARS-CoV-2 virus seems to enhance a tendency toward blood clotting—a problem addressed in our Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership. The partnership recently initiated a trial of blood thinners. That trial will start out by focusing on newly diagnosed outpatients and hospitalized patients, but will go on to include a component related to convalescence.

Moving forward, it will be important to conduct larger and longer-term studies of COVID-19 recovery in people of diverse backgrounds to continue to learn more about what it means to survive COVID-19. The new findings certainly indicate that for many people who’ve been hospitalized with COVID-19, regaining normal lung function may take a while. As we learn even more about the underlying causes and long-term consequences of this new infectious disease, let’s hope it will soon lead to insights that will help many more COVID-19 long-haulers and their concerned loved ones breathe easier.

Reference:

[1] Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. Zhao YM, Shang YM, Song WB, Li QQ, Xie H, Xu QF, Jia JL, Li LM, Mao HL, Zhou XM, Luo H, Gao YF, Xu AG. EClinicalMedicine.2020 Aug 25:100463

Links:

Coronavirus (COVID-19) (NIH)

How the Lungs Work (National Heart, Lung, and Blood Institute/NIH)

Computed Tomography (CT) (National Institute of Biomedical Imaging and Bioengineering/NIH)

Zhengzhou University (Zhengzhou City, Henan Province, China)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)


Study Ties COVID-19-Related Syndrome in Kids to Altered Immune System

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Very sick child
Credit: iStock/Sasiistock

Most children infected with SARS-CoV-2, the virus that causes COVID-19, develop only a mild illness. But, days or weeks later, a small percentage of kids go on to develop a puzzling syndrome known as multisystem inflammatory syndrome in children (MIS-C). This severe inflammation of organs and tissues can affect the heart, lungs, kidneys, brain, skin, and eyes.

Thankfully, most kids with MIS-C respond to treatment and make rapid recoveries. But, tragically, MIS-C can sometimes be fatal.

With COVID-19 cases in children having increased by 21 percent in the United States since early August [2], NIH and others are continuing to work hard on getting a handle on this poorly understood complication. Many think that MIS-C isn’t a direct result of the virus, but seems more likely to be due to an intense autoimmune response. Indeed, a recent study in Nature Medicine [1] offers some of the first evidence that MIS-C is connected to specific changes in the immune system that, for reasons that remain mysterious, sometimes follow COVID-19.

These findings come from Shane Tibby, a researcher at Evelina London Children’s Hospital, London. United Kingdom; Manu Shankar-Hari, a scientist at Guy’s and St Thomas’ NHS Foundation Trust, London; and colleagues. The researchers enlisted 25 children, ages 7 to 14, who developed MIS-C in connection with COVID-19. In search of clues, they examined blood samples collected from the children during different stages of their care, starting when they were most ill through recovery and follow-up. They then compared the samples to those of healthy children of the same ages.

What they found was a complex array of immune disruptions. The children had increased levels of various inflammatory molecules known as cytokines, alongside raised levels of other markers suggesting tissue damage—such as troponin, which indicates heart muscle injury.

The neutrophils, monocytes, and other white blood cells that rapidly respond to infections were activated as expected. But the levels of certain white blood cells called T lymphocytes were paradoxically reduced. Interestingly, despite the low overall numbers of T lymphocytes, particular subsets of them appeared activated as though fighting an infection. While the children recovered, those differences gradually disappeared as the immune system returned to normal.

It has been noted that MIS-C bears some resemblance to an inflammatory condition known as Kawasaki disease, which also primarily affects children. While there are similarities, this new work shows that MIS-C is a distinct illness associated with COVID-19. In fact, only two children in the study met the full criteria for Kawasaki disease based on the clinical features and symptoms of their illness.

Another recent study from the United Kingdom, reported several new symptoms of MIS-C [3]. They include headaches, tiredness, muscle aches, and sore throat. Researchers also determined that the number of platelets was much lower in the blood of children with MIS-C than in those without the condition. They proposed that evaluating a child’s symptoms along with his or her platelet level could help to diagnose MIS-C.

It will now be important to learn much more about the precise mechanisms underlying these observed changes in the immune system and how best to treat or prevent them. In support of this effort, NIH recently announced $20 million in research funding dedicated to the development of approaches that identify children at high risk for developing MIS-C [4].

The hope is that this new NIH effort, along with other continued efforts around the world, will elucidate the factors influencing the likelihood that a child with COVID-19 will develop MIS-C. Such insights are essential to allow doctors to intervene as early as possible and improve outcomes for this potentially serious condition.

References:

[1] Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Carter MJ, Fish M, Jennings A, Doores KJ, Wellman P, Seow J, Acors S, Graham C, Timms E, Kenny J, Neil S, Malim MH, Tibby SM, Shankar-Hari M. Nat Med. 2020 Aug 18.

[2] Children and COVID-19: State-Level Data Report. American Academy of Pediatrics. August 24, 2020.

[3] Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. Swann OV, Holden KA, Turtle L, Harrison EW, Docherty AB, Semple MG, et al. Br Med J. 2020 Aug 17.

[4] NIH-funded project seeks to identify children at risk for MIS-C. NIH. August 7, 2020.

Links:

Coronavirus (COVID-19) (NIH)

Kawasaki Disease (Genetic and Rare Disease Information Center/National Center for Advancing Translational Sciences/NIH)

Shane Tibby (Evelina London Children’s Hospital, London)

Manu Shankar-Hari (King’s College, London)

NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of the Director; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute on Drug Abuse; National Institute of Minority Health and Health Disparities; Fogarty International Center


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