Scientists identify characteristics to better define long COVID

A research team supported by the National Institutes of Health has identified characteristics of people with long COVID and those likely to have it.

Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient.NIAID

Scientists, using machine learning techniques, analyzed an unprecedented collection of electronic health records (EHRs) available for COVID-19 research to better identify who has long COVID. Exploring de-identified EHR data in the National COVID Cohort Collaborative (N3C), a national, centralized public database led by NIH’s National Center for Advancing Translational Sciences (NCATS), the team used the data to find more than 100,000 likely long COVID cases as of October 2021 (as of May 2022, the count is more than 200,000). The findings appear in The Lancet Digital Health.

Long COVID is marked by wide-ranging symptoms, including shortness of breath, fatigue, fever, headaches, “brain fog” and other neurological problems. Such symptoms can last for many months or longer after an initial COVID-19 diagnosis. One reason long COVID is difficult to identify is that many of its symptoms are similar to those of other diseases and conditions. A better characterization of long COVID could lead to improved diagnoses and new therapeutic approaches.

“It made sense to take advantage of modern data analysis tools and a unique big data resource like N3C, where many features of long COVID can be represented,” said co-author Emily Pfaff, Ph.D., a clinical informaticist at the University of North Carolina at Chapel Hill.

The N3C data enclave currently includes information representing more than 13 million people nationwide, including nearly 5 million COVID-19-positive cases. The resource enables rapid research on emerging questions about COVID-19 vaccines, therapies, risk factors and health outcomes.

The new research is part of a related, larger trans-NIH initiative, Researching COVID to Enhance Recovery (RECOVER), which aims to improve the understanding of the long-term effects of COVID-19, called post-acute sequelae of SARS-CoV-2 infection (PASC). RECOVER will accurately identify people with PASC and develop approaches for its prevention and treatment. The program also will answer critical research questions about the long-term effects of COVID through clinical trials, longitudinal observational studies, and more.

In the Lancet study, Pfaff, Melissa Haendel, Ph.D., at the University of Colorado Anschutz Medical Campus, and their colleagues examined patient demographics, health care use, diagnoses and medications in the health records of 97,995 adult COVID-19 patients in the N3C. They used this information, along with data on nearly 600 long COVID patients from three long COVID clinics, to create three machine learning models to identify long COVID patients.

In machine learning, scientists “train” computational methods to rapidly sift through large amounts of data to reveal new insights — in this case, about long COVID. The models looked for patterns in the data that could help researchers both understand patient characteristics and better identify individuals with the condition.

The models focused on identifying potential long COVID patients among three groups in the N3C database: All COVID-19 patients, patients hospitalized with COVID-19, and patients who had COVID-19 but were not hospitalized. The models proved to be accurate, as people identified as at risk for long COVID were similar to patients seen at long COVID clinics. The machine learning systems classified approximately 100,000 patients in the N3C database whose profiles were close matches to those with long COVID. 

“Once you’re able to determine who has long COVID in a large database of people, you can begin to ask questions about those people,” said Josh Fessel, M.D., Ph.D., senior clinical advisor at NCATS and a scientific program lead in RECOVER. “Was there something different about those people before they developed long COVID? Did they have certain risk factors? Was there something about how they were treated during acute COVID that might have increased or decreased their risk for long COVID?”

The models searched for common features, including new medications, doctor visits and new symptoms, in patients with a positive COVID diagnosis who were at least 90 days out from their acute infection. The models identified patients as having long COVID if they went to a long COVID clinic or demonstrated long COVID symptoms and likely had the condition but hadn’t been diagnosed.

“We want to incorporate the new patterns we’re seeing with the diagnosis code for COVID and include it in our models to try to improve their performance,” said the University of Colorado’s Haendel. “The models can learn from a greater variety of patients and become more accurate. We hope we can use our long COVID patient classifier for clinical trial recruitment.”

NIH begins clinical trial evaluating second COVID-19 booster shots in adults

A Phase 2 clinical trial evaluating various additional COVID-19 booster shots has begun enrolling adult participants in the United States. The trial aims to understand if different vaccine regimens—prototype and variant vaccines alone and in combinations—can broaden immune responses in adults who already have received a primary vaccination series and a first booster shot. The study, known as the COVID-19 Variant Immunologic Landscape (COVAIL) trial, is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Colorized scanning electron micrograph of a cell (purple) infected with a variant strain of SARS-CoV-2 virus particles (pink), isolated from a patient sample. NIAID

“We are looking beyond the Omicron variant to determine the best strategy to protect against future variants,” said NIAID Director Anthony S. Fauci, M.D. “This trial will help us understand if we can use prototype and variant vaccines alone or together to shift immune responses to cover existing and emerging COVID-19 variants.”

Despite waning protection against infection and mild illness during the Omicron wave, COVID-19 vaccines available in the United States so far have maintained durable protection against severe COVID-19. However, NIAID is preparing for the possibility of future variants evading protection against currently available COVID-19 vaccines.

COVID-19 vaccine manufacturers can adjust prototype vaccines to target specific variants, a process similar to how manufacturers update seasonal influenza vaccines every year to target circulating strains. However, predicting if, when and where new COVID-19 variants will emerge and how they will affect the population, remains challenging. Studies(link is external) indicate that Omicron has a combination of mutations that make it substantially different from prior SARS-CoV-2 variants. Should a new variant emerge that more closely resembles ancestral SARS-CoV-2 or, for example, the Delta variant, an Omicron-specific vaccine may not offer substantial protection. An individual’s response to booster shots may also be impacted by their history of prior infection and vaccination, or both, and what type of COVID-19 vaccines they received.

Vaccine manufacturers have previously studied some variant vaccine candidates and are currently conducting clinical trials of Omicron-specific vaccines. The COVAIL trial will gather data on the immune responses induced by prototype vaccines and variant vaccine candidates—including bivalent vaccines, which target two SARS-CoV-2 variants—to inform booster shot recommendations.

The first stage of this trial is being conducted in collaboration with Moderna, Inc., based in Cambridge, Massachusetts, and Moderna is manufacturing the study vaccines that will be administered. The trial will be adapted to enroll more participants to evaluate additional vaccine platforms and variant vaccines from other manufacturers as needed to further inform public health decisions. Participants will be monitored for symptoms and adverse events following vaccination and will be asked to return to the clinic during set times over the course of 12-14 months to provide blood samples. Investigators will evaluate the samples in the laboratory to measure and characterize immune responses to SARS-CoV-2 strains. Investigators aim to have initial findings available by August 2022.

Nadine Rouphael, M.D., director of the Hope Clinic at the Emory Vaccine Center in Atlanta, and Angela Branche, M.D., associate professor of medicine at the University of Rochester Medical Center in New York, are leading the trial. Site investigators at 24 clinics are enrolling 600 participants 18 years and older who already have received a primary COVID-19 vaccination series and booster shot. Participants are randomly assigned to one of six vaccine regimens:

People from racial, ethnic, and other groups report frequent COVID-19–related discrimination

People from all major racial and ethnic minority population groups in the United States report experiencing more COVID-19–related discrimination than white adults, a new study shows.

COVID-19-related discrimination includes experiences of being threatened or harassed based on someone’s perception of another having COVID-19. To date, this is the largest study, with the most diverse participants, to examine discrimination related to COVID-19. The study was led by Paula D. Strassle, Ph.D., of the National Institute on Minority Health and Health Disparities (NIMHD), part of the National Institutes of Health, and was published in the American Journal of Public Health on Feb. 23, 2022.

In the study, researchers measured the prevalence of COVID-19–related discrimination in all major racial and ethnic groups in the United States, using data from the COVID-19’s Unequal Racial Burden (CURB) survey. They also analyzed the impact of other social and demographic factors on COVID-19–related discrimination. People from groups that have been marginalized, such as those who speak little to no English and those with lower levels of education, were also found to face more discrimination due to the pandemic.

Researchers collected information from 5,500 American Indian/Alaska Native, Asian, Black/African American, Hawaiian and Pacific Islander, Latino, white, and multiracial adults. The online survey was administered by YouGov from December 2020 to February 2021 and was available in English and Spanish. The survey asked whether participants had experienced COVID-19–related discriminatory behaviors, such as being called names or insulted, being threatened or harassed, or hearing racist comments, because the perpetrator thought the participant had COVID-19. The survey also asked whether participants felt that others acted afraid of them because they belonged to a racial/ethnic group misconceived to get COVID-19 more often.

Results showed that 22.1% of participants had experienced COVID-19–related discriminatory behaviors, and 42.7% of participants reported that people acted afraid of them. When compared to white adults, people from all racial and ethnic minority groups were more likely to have experienced COVID-19–related discrimination. Participants who identified as Asian or American Indian/Alaska Native were most likely to have experienced this hostile behavior, and participants who identified as Hawaiian or Pacific Islander or Latino were also highly likely to have experienced discrimination. Higher rates of discrimination affected participants who lived in a big city; in a rural area; or in Alabama, Kentucky, Mississippi, or Tennessee.

The results suggest that the COVID-19 pandemic has worsened existing resentment toward racial and ethnic minorities and other minority populations in the United States. The study showcases the need for careful and responsible public health messaging during public health crises to help prevent and address discrimination against groups that have been marginalized.

France and WHO sign new agreement to reinforce health systems to combat COVID-19

The Government of France and WHO have announced a new €50 million contribution agreement that will help countries’ health systems overcome bottlenecks in the COVID-19 response and speed up equitable access to testing, treatments, and vaccines.

WHO is very grateful to the Government of France for its continued commitment to global unity in the response to the COVID-19 pandemic. France has taken a leading role in supporting WHO’s work through the ACT Accelerator, which is crucial for WHO to achieve its mission and safeguard the lives of the most vulnerable around the world.

– Dr Tedros Adhanom Ghebreyesus, WHO Director-General

The agreement, disclosed on the sidelines of the ministerial conference of foreign ministers and health ministers in Lyon, France, aims to support the work of WHO and co-convener’s work in the Health Systems and Response Connector (HSRC) of the Access to COVID-19 Tools Accelerator (ACT-A), aligned with the WHO’s COVID-19 Strategic Preparedness and Response Plan (SPRP).

The HSRC works to ensure that countries have the technical, operational, and financial resources to acquire and efficiently use vaccines and other COVID-19 tools.

France’s contribution will help accelerate equitable access to all COVID-19 tools, by looking at each country’s health system’s bottlenecks and identifying the right responses and solutions to them.

The contribution will work through the HSRC to help countries turn vaccines into well-prioritized vaccination campaigns; turn tests into effective test-and-treat approaches; pursue community-based testing strategies to support public health measures and the platform for disease surveillance, and turn therapeutics into life-saving clinical pathways. This means strengthening national response mechanisms and reinforcing health systems.

H.E. Mr. Jean-Yves Le Drian, Foreign Minister of France said: “Global health is of critical importance to the French presidency of the European Union. This support to WHO aims to provide additional support to countries’ health systems; strengthen cooperation between actors and coordination between ACT-A components; to enhance dialogue with all stakeholders including the civil society and recipient countries; and to accelerate equitable access to new COVID-19 tools and ensure they are made available at a scale and scope in order to save millions of lives.”

France shares key health priorities with WHO, adopting a cross-cutting approach and prioritizing universal health coverage as part of the 2030 Sustainable Development Agenda.

In January 2020, France and WHO signed a new framework agreement for 2020-2025, confirming France’s role as a key actor in global health, along with its strong support for WHO’s Thirteenth General Programme of Work, a five-year strategy that aims to ensure healthy lives and well-being for people of all ages.

Scientists pinpoint mechanisms associated with severe COVID-19 blood clotting

After studying blood samples from 244 patients hospitalized for COVID-19, a group of researchers, including those who work at the National Institutes of Health, identified “rogue antibodies” that correlate with severe illness and may help explain mechanisms associated with severe blood clotting.

The researchers found circulating antiphospholipid antibodies, which can be more common among people with autoimmune disorders, such as lupus. However, these “autoantibodies,” which target a person’s own organs and systems, can also be activated in response to viral infections and activate other immune responses.
 

Scientists compared the blood samples to those from healthy controls and found the COVID-19 samples contained higher levels of the antibody IgG, which works with other immune cells, such as IgM, to respond to immune threats. Higher levels of IgG were also associated with COVID-19 disease severity, such as in patients who required breathing assistance. The researchers observed similar patterns, but to a lesser extent, after analyzing blood samples from 100 patients hospitalized for sepsis, which can leave the body in inflammatory shock following a bacterial or viral infection.  

IgG helps bridge a gap between innate and adaptive immune responses – a process that helps the body recognize, respond to, and remember danger. In normal cases, these features help protect the body from illness and infection. However, in some cases, this response can become hyperextended or altered and exacerbate illness. A unique finding from this study is that when researchers removed IgG from the COVID-19 blood samples, they saw molecular indicators of “blood vessel stickiness” fall. When they added these same IgG antibodies to the control samples, they saw a blood vessel inflammatory response that can lead to clotting.  
 
Since every organ has blood vessels in it, circulating factors that lead to the “stickiness” of healthy blood vessels during COVID-19 may help explain why the virus can affect many organs, including the heart, lungs, and brain. A query of this study was evaluating “upstream” factors involved with severe blood clotting and inflammation among people with severe COVID-19 illness.   
 

The researchers note future studies could explore the potential benefits of screening patients with COVID-19 or other forms of critical illness for antiphospholipids and other autoantibodies and at earlier points of infection. This may help identify patients at risk for extreme blood clotting, vascular inflammation, and respiratory failure. Corresponding studies could then assess the potential benefits of providing these patients with treatments to protect blood vessels or fine-tune the immune system.  

COVID-19 increases the risk of pregnancy complications

Pregnant women with COVID-19 appear to be at greater risk for common pregnancy complications — in addition to health risks from the virus — than pregnant women without COVID-19, suggests a study funded by the National Institutes of Health.

Pregnant women with COVID-19 appear to be at greater risk for common pregnancy complications

The study, which included nearly 2,400 pregnant women infected with SARS-CoV-2, found that those with moderate to severe infection were more likely to have a cesarean delivery, to deliver preterm, to die around the time of birth, or to experience serious illness from hypertensive disorders of pregnancy, postpartum hemorrhage, or from infection other than SARS-CoV-2. They were also more likely to lose the pregnancy or to have an infant die during the newborn period. Mild or asymptomatic infection was not associated with increased pregnancy risks.

“The findings underscore the need for women of child-bearing age and pregnant individuals to be vaccinated and to take other precautions against becoming infected with SARS-CoV-2,” said Diana Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which funded the study. “This is the best way to protect pregnant women and their babies.”

The study was conducted by Torri D. Metz, M.D., of the University of Utah, Salt Lake City, and colleagues in the NICHD Maternal-Fetal Medicine Units Network. It appears in the Journal of the American Medical Association. Additional funding was provided by NIH’s National Center for Advancing Translational Sciences.

The study included more than 13,000 pregnant individuals from 17 U.S. hospitals, approximately 2,400 of whom were infected with SARS-CoV-2. Participants delivered between March 1 and December 31, 2020, before SARS-CoV-2 vaccination was available. The researchers compared outcomes among those with COVID-19 to those from uninfected patients and tabulated the study results as a primary outcome — whether the patient had died from any cause or had a serious illness or condition related to common obstetric complications. They also evaluated the results in terms of several secondary outcomes, including cesarean delivery, preterm birth, and fetal and newborn death.

Global growth to slow through 2023 due to continued COVID-19 flare-ups – New Global Economic Prospects report

After rebounding to an estimated 5.5 percent in 2021, global growth is expected to decelerate markedly to 4.1 percent in 2022, reflecting continued COVID-19 flare-ups, diminished fiscal support, and lingering supply bottlenecks, according to a New Global Economic Prospects report.

The COVID-19 upsurge comes as the vaccine supply crunch persists.. Photo credit: United Nations

In contrast to that in advanced economies, output in emerging market and developing economies (EMDEs) will remain substantially below the pre-pandemic trend over the forecast horizon.

The global outlook is clouded by various downside risks, including renewed COVID-19 outbreaks due to Omicron or new virus variants, the possibility of de-anchored inflation expectations, and financial stress in a context of record-high debt levels.

The report states that if some countries eventually require debt restructuring, this will be more difficult to achieve than in the past.

Climate change may increase commodity price volatility, creating challenges for the almost two-thirds of EMDEs that rely heavily on commodity exports and highlighting the need for asset diversification. Social tensions may heighten as a result of the increase in between-country and within-country inequality caused by the pandemic. Given limited policy space in EMDEs to support activity if needed, these downside risks increase the possibility of a hard landing.

These challenges underscore the importance of strengthened global cooperation to foster rapid and equitable vaccine distribution, proactive measures to enhance debt sustainability in the poorest countries, redoubled efforts to tackle climate change and within-country inequality, and an emphasis on growth-enhancing policy interventions to promote green, resilient, and inclusive development and on reforms that broaden economic activity to decouple from global commodity markets.

Climate change may increase commodity price volatility

The near-term outlook for global growth is somewhat weaker, and for global inflation notably higher, than previously envisioned, owing to pandemic resurgence, higher food and energy prices, and more pernicious supply disruptions. Global growth is projected to soften further to 3.2 percent in 2023, as pent-up demand wanes and supportive macroeconomic policies continue to be unwound.

However, the report further noted that although output and investment in advanced economies are projected to return to pre-pandemic trends next year, in emerging market and developing economies (EMDEs)— particularly in small states and fragile and conflict -afflicted countries—they will remain markedly below, owing to lower vaccination rates, tighter fiscal and monetary policies, and more persistent scarring from the pandemic.