NIH observational study of coronavirus infection and multisystem inflammatory syndrome in children begins

An observational study has launched to evaluate the short- and long-term health outcomes of SARS-CoV-2 infection in children, including multisystem inflammatory syndrome in children (MIS-C), and to characterize the immunologic pathways associated with different disease presentations and outcomes.

l Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of a cell (pink) heavily infected with SARS-CoV-2 virus particles (teal and purple), isolated from a patient sampleNIAID

SARS-CoV-2 is the virus that causes COVID-19. The study, called the Pediatric Research Immune Network on SARS-CoV-2 and MIS-C (PRISM), will enroll at least 250 children and young adults ages 20 years or younger from diverse racial and ethnic backgrounds at approximately 20 sites nationwide.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is sponsoring and funding the study. The PRISM study is part of a research effort led by NIH’s National Heart, Lung, and Blood Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development to understand MIS-C.

Although SARS-CoV-2 infection usually causes either no illness or only mild illness in children, some children become seriously ill at the time of infection, while others who initially have no symptoms later develop MIS-C. MIS-C is a life-threatening condition marked by severe inflammation of one or more parts of the body, including the heart, lungs, kidneys, brain, skin, eyes and gastrointestinal organs. The syndrome typically begins several weeks after SARS-CoV-2 exposure and disproportionately affects Black and Hispanic children.

“It is critical that we learn how to prevent and treat this rare but very serious syndrome in children,” said NIAID Director Anthony S. Fauci, M.D. “Information gathered through the PRISM study may ultimately help clinicians diagnose and treat MIS-C as well as predict which children are susceptible to the disease.” 

The PRISM study aims to fill gaps in understanding of the clinical spectrum of COVID-19 in children and young adults, the long-term outcomes of SARS-CoV-2 infection in these populations, and the underlying immunologic basis of MIS-C. It is led by clinical protocol chair Steven A. Webber, M.B.Ch.B., M.R.C.P., chair of the department of pediatrics in Monroe Carell Jr. Children’s Hospital at Vanderbilt in Nashville, Tennessee.

The PRISM study team is enrolling children and young adult volunteers with detectable SARS-CoV-2 in respiratory samples, with symptoms of MIS-C, or both. Participants will be followed for at least one year.

The study has two main goals. The first is to determine the proportion of children who die, are re-hospitalized after an initial hospital admission, or have major health complications due to SARS-CoV-2 at six and 12 months after initial presentation with COVID-19, MIS-C, or both. The second is to determine the immunologic mechanisms and characteristics associated with different forms of MIS-C and COVID-19 in children. Results are expected in mid-2022.

Novel Coronavirus Appears to hijack and exit cells as it spreads through the body – NIH findings

Researchers at the US National Institutes of Health have found out that the coronavirus deactivates the cells’ disease-fighting machinery that destroys viruses and other pathogens before they leave the cells, allowing it to freely spread throughout the body.

Illustration shows components of the lysosome exocytosis pathway, which coronaviruses use to exit cells. Also shown are components of the normal biosynthetic secretory pathway. NIH Medical Arts

The researchers discovered a biological pathway that the novel coronavirus appears to use to hijack and exit cells as it spreads through the body. A better understanding of this important pathway may provide vital insight in stopping the transmission of the virus—SARS-CoV-2—which causes COVID-19 disease.

In cell studies, the researchers showed for the first time that the coronavirus can exit infected cells through the lysosome, an organelle known as the cells’ “trash compactor.” Normally the lysosome destroys viruses and other pathogens before they leave the cells. However, the researchers found that the coronavirus deactivates the lysosome’s disease-fighting machinery, allowing it to freely spread throughout the body.

Targeting this lysosomal pathway could lead to the development of new, more effective antiviral therapies to fight COVID-19. The findings, published today in the journal Cell(link is external), come at a time when new coronavirus cases are surging worldwide, with related U.S. deaths nearing 225,000.

Scientists have known for some time that viruses enter and infect cells and then use the cell’s protein-making machinery to make multiple copies of themselves before escaping the cell. However, researchers have only a limited understanding of exactly how viruses exit cells.

Conventional wisdom has long held that most viruses—including influenza, hepatitis C, and West Nile—exit through the so-called biosynthetic secretory pathway. That’s a central pathway that cells use to transport hormones, growth factors, and other materials to their surrounding environment. Researchers have assumed that coronaviruses also use this pathway.

But in a pivotal experiment, Nihal Altan-Bonnet, Ph.D., chief of the Laboratory of Host-Pathogen Dynamics at the NIH’s National Heart, Lung, and Blood Institute (NHLBI) and her post-doctoral fellow Sourish Ghosh, Ph.D., the study’s main authors, found something different. She and her team exposed coronavirus-infected cells (specifically, mouse hepatitis virus) to certain chemical inhibitors known to block the biosynthetic pathway. 

“To our shock, these coronaviruses got out of the cells just fine,” Altan-Bonnet said. “This was the first clue that maybe coronaviruses were using another pathway.”

To look for that pathway, the researchers designed additional experiments using microscopic imaging and virus-specific markers involving human cells. They discovered that coronaviruses somehow target the lysosomes, which are highly acidic, and congregate there.

That finding raised yet another question for Altan-Bonnet’s team: If coronaviruses are accumulating in lysosomes and lysosomes are acidic, why are the coronaviruses not destroyed before exiting?

In a series of advanced experiments, the researchers demonstrated that lysosomes get de-acidified in coronavirus-infected cells, significantly weakening the activity of their destructive enzymes. As a result, the viruses remain intact and ready to infect other cells when they exit.

“These coronaviruses are very sneaky,” Altan-Bonnet said. “They’re using these lysosomes to get out, but they’re also disrupting the lysosome so it can’t do its job or function.”

The researchers also discovered that disrupting normal lysosome function appears to harm the cells’ immunological machinery. “We think this very fundamental cell biology finding could help explain some of the things people are seeing in the clinic regarding immune system abnormalities in COVID patients,” Altan-Bonnet said. This includes cytokine storms, in which an excess of certain pro-inflammatory proteins in the blood of COVID patients overwhelm the immune system and cause high death rates.

Now that this mechanism has been identified, researchers may be able to find ways to disrupt this pathway and prevent lysosomes from delivering viruses to the outside of the cell; or re-acidify lysosomes in order to restore their normal functions in coronavirus-infected cells so they can fight COVID. The authors have already identified one experimental enzyme inhibitor that potently blocks coronaviruses from getting out of the cell.

“The lysosome pathway offers a whole different way of thinking about targeted therapeutics,” she said, adding that further studies will be needed to determine if such interventions will be effective and whether existing drugs can help block this pathway. She notes the findings could go a long way toward stemming future pandemics caused by other coronaviruses that may emerge.

Research reported in this study was funded by the Division of Intramural Research of NHLBI, part of the National Institutes of Health. Additionally, the research was supported by NIH grants including NIH R01 AI091985-05; NIH R01 NS36592; F32-AI113973; NIH R37GM058615; and NIH R01AI135270. All other co-authors were supported by intramural NIH and National Cancer Institute funds. 

NIH to test one-dose antibiotic for the prevention of maternal and infant sepsis

Researchers supported by the National Institutes of Health and the Bill & Melinda Gates Foundation will assess whether a single oral dose of the antibiotic azithromycin during labor reduces the risk of maternal and infant bacterial infection and death in seven low- and middle-income countries.

“We urgently need effective interventions to reduce the death toll of pregnancy-related infections worldwide,” said Diana W. Bianchi, M.D., NICHD Director. “This study allows us to test a low-cost intervention that has shown promise in a smaller study.”

The clinical trial is funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Gates Foundation. The trial will be conducted by researchers in NICHD’s Global Network for Women’s and Children’s Health Research, or NICHD Global Network.

Maternal death from sepsis — a system-wide reaction to bacterial and other infections — is higher in many low- and middle-income countries, compared to wealthy countries. This higher death rate results from a combination of factors, including a longer time to diagnosis, lack of access to timely drug treatment and chronic malnourishment. Infection during pregnancy and in the weeks after birth account for roughly 10% of maternal deaths worldwide, according to the World Health Organization. Infection accounts for 16% of newborn deaths worldwide.

Azithromycin, an antibiotic effective against a broad range of bacteria, has been shown(link is external) to protect against infection resulting from cesarean delivery. The drug is low-cost and can be kept at room temperature, which makes it suitable for parts of the world where refrigeration isn’t always available. An earlier study of more than 800 women in The Gambia found that administering azithromycin to pregnant women at the beginning of labor reduced maternal and infant infections, compared to a group that received a placebo. Azithromycin and other antibiotics are not effective against COVID-19 and other diseases caused by viruses.

The current study plans to enroll up to 34,000 women at NICHD Global Network sites in Bangladesh, the Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan and Zambia. Half of the women will receive a single 2-gram dose of oral azithromycin, and the other half will receive a placebo. The women and their infants will be monitored for fever and other signs of infection during their hospital stay and again at one week and six weeks after giving birth. The study will also include records of unscheduled visits to health facilities outside of the network sites.

“The NICHD Global Network provides the expertise and infrastructure needed to carry out this essential clinical trial,” said lead investigator Waldemar Carlo, M.D., of the Neonatology Division of the University of Alabama at Birmingham. “We anticipate that this study will provide important data to help us improve the standard of maternal care in low- and middle-income countries.”

The Foundation for the National Institutes of Health, a not-for-profit organization that manages alliances with public and private institutions in support of the NIH mission, provided funding for the study with a grant from the Gates Foundation.

NIH mobilizes national innovation initiative for COVID-19 diagnostics

The National Institutes of Health announced a new initiative aimed at speeding innovation, development and commercialization of COVID-19 testing technologies, a pivotal component needed to return to normal during this unprecedented global pandemic.

With a $1.5 billion investment from federal stimulus funding, the newly launched Rapid Acceleration of Diagnostics (RADx) initiative will infuse funding into early innovative technologies to speed development of rapid and widely accessible COVID-19 testing. At the same time, NIH will seek opportunities to move more advanced diagnostic technologies swiftly through the development pipeline toward commercialization and broad availability. NIH will work closely with the U.S. Food and Drug Administration, the Centers for Disease Control and Prevention and the Biomedical Advanced Research and Development Authority (BARDA) to advance these goals.

The stimulus investment supercharges NIH’s strong research efforts already underway focused on prevention and treatment of COVID-19, including the recently announced planned Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership to coordinate the international research response to the pandemic.  

“We need all innovators, from the basement to the boardroom, to come together to advance diagnostic technologies, no matter where they are in development,” said NIH Director Francis S. Collins, M.D., Ph.D. “Now is the time for that unmatched American ingenuity to bring the best and most innovative technologies forward to make testing for COVID-19 widely available.”

As part of this initiative, NIH is urging all scientists and inventors with a rapid testing technology to compete in a national COVID-19 testing challenge for a share of up to $500 million over all phases of development. The technologies will be put through a highly competitive, rapid three-phase selection process to identify the best candidates for at-home or point-of-care tests for COVID-19. Finalists will be matched with technical, business and manufacturing experts to increase the odds of success. If certain selected technologies are already relatively far along in development, they can be put on a separate track and be immediately advanced to the appropriate step in the commercialization process. The goal is to make millions of accurate and easy-to-use tests per week available to all Americans by the end of summer 2020, and even more in time for the flu season.

“Americans are innovators and makers,” said Bruce J. Tromberg, Ph.D., director of NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB). “We need American tech experts, innovators and entrepreneurs to step up to one of the toughest challenges we’ve faced as a country, to help get us safely back to public spaces.”

While diagnostic testing has long been a mainstay of public health, newer technologies offer patient- and user-friendly designs, mobile-device integration, reduced cost and increased accessibility both at home and at the point of care. RADx will expand the Point-of-Care Technologies Research Network(link is external) (POCTRN) established several years ago by NIBIB. The network will use a flexible, rapid process to infuse funding and enhance technology designs at key stages of development, with expertise from technology innovators, entrepreneurs and business leaders across the country. POCTRN supports hundreds of investigators from multiple universities and businesses through five technology hubs:

• Emory University/Georgia Institute of Technology, Atlanta
• Johns Hopkins University, Baltimore
• Northwestern University, Evanston, Illinois
• University of Massachusetts Medical School, Worcester
• Consortia for Improving Medicine with Innovation & Technology (CIMIT) at Harvard Medical School/Massachusetts General Hospital, Boston

Led by the Coordinating Center at CIMIT, the network has assembled expert review boards covering scientific, clinical, regulatory and business domains that will rapidly evaluate technology proposals. In order to roll out new products starting at the end of summer/fall 2020, a rapid, parallel process will allow quick throughput of projects. Projects will be assessed at each milestone and must demonstrate significant progress to receive continued support.

COVID-19 workers get training to protect their own health

The National Institutes of Health will launch a website with important educational resources for coronavirus workers dealing with the spread of COVID-19. 

The initiative got underway after Congress passed a supplemental appropriation of $10 million on March 6 for worker-based training to prevent and reduce exposure of hospital employees, emergency first responders, and other workers who are at risk of exposure to coronavirus through their work duties. The law provided a total of $8.3 billion in emergency funding for certain federal agencies to respond to the coronavirus outbreak.

The worker-based training initiative is being led by NIH’s National Institute of Environmental Health Sciences (NIEHS), which has a long-established Worker Training Program (WTP). The program awards grants for training and development of educational resources for employees in high risk occupations who serve the public during emergencies and who need skills to protect their own health as they are potentially exposed to dangerous pathogens, contaminated materials, or infected people. As a part of this effort the WTP also acts as a clearinghouse among grant recipients to broadly share the training and educational resources developed with the grant money.

Joseph “Chip” Hughes, who has led the NIEHS WTP for 31 years, said, “These men and women are so dedicated and as they work so hard to serve and protect the public during this COVID-19 pandemic, I want to make sure they know how to protect their own health too. We don’t need them getting sick, or taking the virus back to their families or their communities.”

With this new supplemental funding from Congress, the NIEHS WTP is creating a COVID-19 virtual safety training initiative for frontline responders including emergency medical personnel, firefighters, law enforcement officers, environmental cleanup workers, high-risk custodial service workers, food processing and delivery workers, water and sewage treatment workers, sanitation workers, and health care facility employees.

The initial focus is to build a virtual safety training delivery platform in partnership with private sector e-learning companies with the capability to deliver synchronized just-in-time web-based training across the country in targeted high-risk industrial sectors. Additionally, a cadre of COVID-19 safety trainers and virtual safety advisors is being created to leverage the delivery of advanced training technology to frontline responders.

After learning of the special appropriation, NIEHS moved quickly to convene a national workshop in partnership with Emory Health Sciences Center on March 17. The workshop titled, “Protecting Infectious Disease Responders During the COVID-19 Outbreak,” used virtual meeting technology to bring together hundreds of the country’s infectious disease experts, nurses and health care providers, emergency response organizations and academic training centers to map out a web-based, technology-assisted training strategy to respond to the escalating need to ensure protections for COVID-19 responders, particularly in health care and emergency response services.

During a recent Congressional hearing on COVID-19 response, NIH Director Francis Collins, M.D., testified that “NIEHS has played a very critical role in training people who can deal with outbreaks.”  He noted the NIEHS WTP previously helped with the Ebola response.

NIH-funded study finds teens prefer mint and mango vaping flavors

A new analysis suggests that teens prefer mint and mango as their vaping flavors of choice for e-cigarettes.

E-cigarette. Photo credit: Medical News Today

 Previous research showed that teens were attracted to nicotine vaping by the candy and fruit-flavored products offered by manufacturers. Products and trends are quickly evolving, and estimates of the specific e-cigarette flavors teens use are lacking; therefore, scientists wanted to find out which flavors are now preferred by teens. The report, published in JAMA, was supported by the National Institute on Drug Abuse (NIDA), the National Cancer Institute (NCI), and the U.S. Food and Drug Administration Center for Tobacco Products. NIDA and NCI are parts of the National Institutes of Health.

The study focused on JUUL products, the most widely used brand, which is available in multiple flavors. Data were from the 2019 Monitoring the Future (MTF) study, which annually surveys eighth, 10th, and 12th grade students in U.S. schools. A randomly-selected third of MTF respondents were asked, “Which JUUL flavor do you use most often?”

The 2019 data suggests that among both 12th and 10th graders, mint and mango ranked first and second (at about 47% and 24% for seniors; 44% and 27% for 10th graders). Among eighth graders, mango was most popular at 34%, followed by mint at 29%. In all grades, fruit flavoring was ranked third, followed by “Other.” Menthol was among the least popular (less than 2.3% for eighth graders; less than 3% for 10th graders and less than 6% for seniors).

The overall 2019 Monitoring the Future vaping data released last month showed a significant increase in past month vaping of nicotine in each of the three grade levels since last year. Additional findings from the 2019 Monitoring the Future Survey, documenting the use of and attitudes about marijuana, alcohol and other drugs, will be released in December.

In rare cases, immune system fails despite HIV suppression

Antiretroviral therapy (ART) is usually very effective at suppressing HIV in the body, allowing a person’s immune system to recover by preventing the virus from destroying CD4+ T cells(link is external).

Colorized scanning electron micrograph of a T lymphocyte.NIAID

Scientists have now identified a rare, paradoxical response to ART known as extreme immune decline, or EXID. Five individuals evaluated at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, experienced a significant decline in CD4+ T cell levels despite suppression of HIV below detectable levels for more than three years, according to a report published online today in JCI Insight.  

The research team was led by Irini Sereti, M.D., chief of the HIV Pathogenesis Section in NIAID’s Laboratory of Immunoregulation, and Andrea Lisco, M.D., Ph.D.

The NIAID researchers found that the immune systems of people with EXID fared even worse than those of another subset of individuals defined as immunological-non-responders, or INRs, who respond inadequately to ART.  INR participants consistently taking ART for four years had CD4+ T cell counts that increased on average by 193 cells per microliter (µL) of blood.  Participants who responded normally to ART increased their CD4+ T cell count by more than twice that amount. In contrast, the five participants with EXID experienced an average decline of 157 CD4+ T cells/µL while consistently maintaining viral suppression on ART.

According to the NIAID team, there seems to be no single cause of EXID among the five individuals studied. Their analyses revealed that genes influencing immune cell activity and autoimmunity—the immune system attacking a body’s own healthy tissue—may play a role. Specifically, two of the individuals with EXID produced antibodies that attacked their own T cells, while two others had overactive cellular immune responses that lead to increased inflammation. All five participants with EXID had HIV strains other than clade B HIV (the most common strain circulating in North America and Europe), indicating that certain combinations of an individual’s genes and the HIV strain may be associated with EXID. While EXID is likely an extremely rare response to ART, the researchers indicate that studying this phenomenon may further illuminate CD4+ T cell reconstitution and inflammation in HIV disease and suggest possible treatment strategies for INRs and individuals with EXID.