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Medicine

A COVID-19 Biomarker: Low Blood Levels of Sphingosine Predict Symptomatic Infections (Medicine)

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Researchers remain perplexed as to why some patients infected with SARS-CoV-2, the virus responsible for COVID-19, remain asymptomatic while other patients develop severe disease symptoms. This question is once again at the front of mind as the Delta variant spreads across the country. In a new retrospective study, researchers at the Medical University of South Carolina (MUSC) discovered a specific and sensitive biomarker in blood samples that predicts which patients will develop COVID-19 symptoms. Their results, published online on July 9 in Scientific Reports, show that reduced levels of a specific lipid, sphingosine, are significantly associated with developing COVID-19 symptoms. Conversely, elevated levels of sphingosine, as well as a protein involved in its production, acid ceramidase (AC), are associated with asymptomatic infections.

“We developed this project at a time when there wasn’t a successful vaccine,” said Besim Ogretmen, Ph.D., director of the Lipidomics Shared Resource at Hollings Cancer Center and leader of the Hollings Developmental Cancer Therapeutics Research Program. “We wanted to contribute to the field and know which patients who were exposed to this virus would be symptomatic versus asymptomatic.”

Over the past 16 months several waves of SARS-CoV-2 infections in the U.S. have resulted in more than 35 million cases and almost 630,000 deaths. Despite the development of multiple safe and effective vaccines, we are currently experiencing another wave of infections.

The mortality of COVID-19 is thought to result from an overactive immune response to the virus in the lungs of infected patients that causes severe respiratory distress. However, symptoms vary widely, and scientists and clinicians don’t understand why some patients develop severe symptoms while others remain asymptomatic.

“If we can separate asymptomatic patients from symptomatic patients, we can use limited remedies and resources for patients who are more vulnerable.”, said Dr. Besim Ogretmen.

It is known that sphingolipids, a class of molecules that are important for the integrity of the cell membrane and communication between cells, can regulate inflammation and the immune system in response to various infections. The Ogretmen laboratory has decades of expertise in analyzing the production and processing of different lipids, including sphingolipids, using a global measurement method called lipidomics.

Using this expertise, the Ogretmen lab undertook an unbiased analysis of COVID-19 patient serum samples from the MUSC COVID-19 Biorepository to look for changes in sphingolipid levels.

The results were striking.

“Just by looking at the data, you can clearly separate the different patient groups, even without doing technical statistical analyses,” said Alhaji Janneh, lead author and graduate student in the Department of Biochemistry and Molecular Biology.

In asymptomatic patients who tested positive for a SARS-CoV-2 antibody, the researchers found a slight increase in serum sphingosine levels – and only sphingosine – compared to patients who tested negative. Remarkably, in patients who developed COVID-19 symptoms, there was a 15-fold reduction in sphingosine levels. Conversely, almost 75% of asymptomatic patients had elevated AC levels while most symptomatic patients had no detectable AC. The presence of serum AC correlates with the increased levels of sphingosine.

“Can this be an alternative way to predict which patients are the most vulnerable to severe disease?” asked Ogretmen, who is also a professor in the Department of Biochemistry and Molecular Biology and the SmartState Endowed Chair in Lipidomics and Drug Discovery. “If we can separate asymptomatic patients from symptomatic patients, we can use limited remedies and resources for patients who are more vulnerable.”

Overall, there is a 99% probability of correctly determining which patients, who have tested positive for SARS-CoV-2 antibodies, will develop disease symptoms versus remain asymptomatic, using blood levels of sphingosine.

These striking results would not have been possible without the MUSC COVID-19 Biorepository and collaboration with the South Carolina Clinical & Translational Research Institute (SCTR). SCTR set up the biorepository to serve as a resource for COVID-19 research, and SCTR co-principal investigator Patrick Flume, M.D. is its director and one of the authors of the article.

Analyzing levels of various lipids from patient samples is expensive and requires sophisticated equipment, making this type of analysis prohibitive under most circumstances. However, the development of an ELISA-based assay – like those used to diagnose HIV infection – to detect levels of AC could provide a cost-effective alternative that could be widely implemented.

There are several outstanding questions remaining. How does vaccination impact sphingosine levels? How do sphingosine levels change with the introduction of more variants? Nevertheless, the ability to identify at-risk patients quickly could vastly improve treatment of COVID-19 and allow for effective distribution of scarce resources.

Featured image: Dr. Besim Ogretmen (left) and graduate student Alhaji Janneh (right) in the laboratory. © MUSC

Reference: Alhaji H. Janneh et al, Alterations of lipid metabolism provide serologic biomarkers for the detection of asymptomatic versus symptomatic COVID-19 patients, Scientific Reports (2021). DOI: 10.1038/s41598-021-93857-7

Provided by MUSC

Medicine

The Diagnosis That Will Save Millions Of Lives From Breast Cancer (Medicine)

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Detection of changes in lung tissue, indicating possible development of cancerous metastases, will allow diagnosis and preventive treatment

A new study from Tel Aviv University has revealed changes in healthy lung tissue, which are a preliminary sign of the possible development of cancer cell metastases. The changes were detected in an area known as the ‘microenvironment’ of the tumor, and found in connective tissue cells called fibroblasts. According to the researchers, understanding the metastatic process and diagnosing it at such an early stage may lead to life-saving preventive treatment.

Decipher the ‘black box’ of breast cancer

The study was led by Prof. Neta Erez, Head of the Department of Pathology at the Sackler Faculty of Medicine , along with a team of researchers in her laboratory, Dr. Ofir Shani and Dr. Yael Raz, as well as other researchers from Tel Aviv University, Tel Aviv Medical Center (Ichilov) , From the Sheba Medical Center and the Weizmann Institute The article was published in the journal eLife .

According to the researchers, in many cancers, including breast cancer, patients do not necessarily die from the primary tumor. The deadly cause, in the end, is the metastases, which reach vital organs and thrive there. Even in a patient who has undergone all the proposed treatments, including surgery to remove the primary tumor, followed by chemotherapy treatments and radiation designed to eliminate its remnants, metastases may appear several years later. In the follow-up methods used today, the metastases are detected when the disease is in an advanced stage, and medicine has no effective solutions.

For this reason, Prof. Erez’s group is researching the ‘black box’ – the same period of time between the apparent recovery and the appearance of the metastases, in order to understand the metastatic process and identify it already in the initial stages. The group’s research in recent years has shown that the target tissues in the organs to which the metastases are destined to reach ‘prepare the area’ for their absorption, and create a ‘friendly environment’ for them long before the metastases themselves appear. In the present study, the team looked for signs of these changes, which may be used in the future to identify the process at an early stage. They focused on connective tissue cells (fiber cells), called fibroblasts and found in, among other things, health.

What happens in the microenvironment of the metastases?

“In normal condition, fibroblasts play a key role in healing wounds and tissue damage, but recent studies have shown that cancer manages to recruit them and cause them to produce a supportive environment for it,” explains Prof. Erez.

The researchers performed sequencing of all expressed genes (transcriptomic sequencing) in fibroblast cells taken from the lungs of mice in a breast cancer model. They compared the results of the flooring in cells sampled from healthy lungs, lungs with micro-metastases (tiny metastases that cannot be detected by conventional clinical trials), and lungs with large metastases, in a state of advanced disease. Based on the changes identified from stage to stage, the researchers were able to characterize for the first time the process that takes place in the microenvironment of the cancer metastases, already in the early stages of preparing the surface for their absorption.

In addition, they specifically identified the proteins that drive the ‘rewiring’ processes in fibroblasts, and found that one of the key proteins in the process is Myc  , which is known as a driving factor in accelerating the division of cancer cells. It now turns out that this protein also plays an important role in the change that occurs in fibroblasts towards the absorption of metastases.

“We have been able to characterize processes that occur in seemingly healthy tissues in preparation for the absorption of cancerous metastases. We believe that in the future our findings could help identify the metastatic process before the metastases themselves reach and take root in the target organ. Of millions of people all over the world, “concludes Prof. Erez.

Featured image: Prof. Neta Erez © Tel Aviv University

Reference: Ophir Shani et al, Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity, eLife (2021). DOI: 10.7554/eLife.60745

Provided by Tel Aviv University

Medicine

New Drug Combo Shows Early Potential For Treating Pancreatic Cancer (Medicine)

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Researchers find three immunotherapy drugs given together can eliminate pancreatic tumors in mice.

Pancreatic cancer, which affects about 60,000 Americans every year, is one of the deadliest forms of cancer. After diagnosis, fewer than 10 percent of patients survive for five years. 

While some chemotherapies are initially effective, pancreatic tumors often become resistant to them. The disease has also proven difficult to treat with newer approaches such as immunotherapy. However, a team of MIT researchers has now developed an immunotherapy strategy and shown that it can eliminate pancreatic tumors in mice.

The new therapy, which is a combination of three drugs that help boost the body’s own immune defenses against tumors, is expected to enter clinical trials later this year.

“We don’t have a lot of good options for treating pancreatic cancer. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it would make a big impact in at least a subset of patients’ lives, but we need to see how it will actually perform in trials.”

Freed-Pastor, who is also a medical oncologist at Dana-Farber Cancer Institute, is the lead author of the new study, which appears today in Cancer Cell. Tyler Jacks, the David H. Koch Professor of Biology and a member of the Koch Institute, is the paper’s senior author.

Immune attack

The body’s immune system contains T cells that can recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that disables these T cells, helping the tumor to survive.

Immune checkpoint therapy (the most common form of immunotherapy currently being used clinically) works by removing the brakes on these T cells, rejuvenating them so they can destroy tumors. One class of immunotherapy drug that has shown success in treating many types of cancer targets the interactions between PD-L1, a cancer-linked protein that turns off T cells, and PD-1, the T cell protein that PD-L1 binds to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, have been approved to treat cancers such as melanoma and lung cancer, but they have very little effect on pancreatic tumors.

Some researchers had hypothesized that this failure could be due to the possibility that pancreatic tumors don’t express as many cancerous proteins, known as neoantigens. This would give T cells fewer targets to attack, so that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be able to identify and destroy tumor cells.

However, some recent studies had shown, and the new MIT study confirmed, that many pancreatic tumors do in fact express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients.

In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Instead, most pancreatic cancer cells express a protein called CD155, which activates a receptor on T cells known as TIGIT.

When TIGIT is activated, the T cells enter a state known as “T cell exhaustion,” in which they are unable to mount an attack on pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, the researchers observed TIGIT expression and T cell exhaustion from about 60 percent of patients, and they also found high levels of CD155 on tumor cells from patients.

“The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells,” Freed-Pastor says. “When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”

Drug combination

The researchers then set out to see if they could use this knowledge to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. They tested a variety of combinations of experimental drugs that inhibit PD-1 and TIGIT, along with another type of drug called a CD40 agonist antibody.

CD40 agonist antibodies, some of which are currently being clinically evaluated to treat pancreatic cancer, are drugs that activate T cells and drive them into tumors. In tests in mice, the MIT team found that drugs against PD-1 had little effect on their own, as has previously been shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was able to halt tumor growth in some animals, but did not substantially shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals given this treatment, and in 25 percent of the mice, the tumors disappeared completely. Furthermore, the tumors did not regrow after the treatment was stopped. “We were obviously quite excited about that,” Freed-Pastor says.

Working with the Lustgarten Foundation for Pancreatic Cancer Research, which helped to fund this study, the MIT team sought out two pharmaceutical companies who between them have a PD-1 inhibitor, TIGIT inhibitor, and CD40 agonist antibody in development. None of these drugs are FDA-approved yet, but they have each reached phase 2 clinical trials. A clinical trial on the triple combination is expected to begin later this year.

“This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease,” Jacks says. “We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research.”

Alongside the clinical trial, the MIT team plans to analyze which types of pancreatic tumors might respond best to this drug combination. They are also doing further animal studies to see if they can boost the treatment’s effectiveness beyond the 50 percent that they saw in this study.

In addition to the Lustgarten Foundation, the research was funded by Stand Up To Cancer, the Howard Hughes Medical Institute, Dana-Farber/Harvard Cancer Center, the Damon Runyon Cancer Research Foundation, and the National Institutes of Health.

Featured image: In this pancreatic tumor, T cells (pink) have infiltrated tumor cells (labeled green) following treatment with a novel combination immunotherapy developed by MIT researchers.Credits:Credit: William Freed-Pastor

Reference: William A. Freed-Pastor, Laurens J. Lambert, Zackery A. Ely, Nimisha B. Pattada, Arjun Bhutkar, George Eng, Kim L. Mercer, Ana P. Garcia, Lin Lin, William M. Rideout, William L. Hwang, Jason M. Schenkel, Alex M. Jaeger, Roderick T. Bronson, Peter M.K. Westcott, Tyler D. Hether, Prajan Divakar, Jason W. Reeves, Vikram Deshpande, Toni Delorey, Devan Phillips, Omer H. Yilmaz, Aviv Regev, Tyler Jacks, The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer, Cancer Cell, 2021, , ISSN 1535-6108, https://doi.org/10.1016/j.ccell.2021.07.007. (https://www.sciencedirect.com/science/article/pii/S1535610821003846)

Provided by MIT

Medicine

Cytotoxic Drugs Can Increase Cancer Cell Resistance (Medicine)

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Cancer cells sometimes develop resistance to the cytotoxic drugs used in chemotherapy. Figuring out why the treatment isn’t working and why it may even defeat its own purpose is therefore important to understand.

“We haven’t understood very much about how this resistance to chemotherapy develops and even less about how the microenvironment in cancer can affect the process,” says Kaisa Lehti, a professor at the Norwegian University of Science and Technology’s (NTNU) Department of Biomedical Laboratory Science.

Lehti has led the work to understand more about how cancerous tissues develop resistance to a particular form of chemotherapy. The University of Helsinki, Karolinska Institutet and NTNU have collaborated on the research. The results have now been published in the well-respected Nature Communications journal.

Standard treatment may fail

Ovarian cancer affects about 500 Norwegian women each year. If the cancer is detected early, almost all patients survive the first five years. But if it is discovered later, the chances of survival are much worse. Finding effective treatment is therefore very important.

One of the standard treatments for ovarian cancer is called platinum chemotherapy. The cytotoxins are so named because they contain platinum compounds. They are often effective in treating various cancers.

Unfortunately, cancer cells often develop resistance to this particular platinum chemotherapy treatment. The solution lies in how the cytotoxin itself can change the cancer cells and their environment.

Cytotoxin changes cancer cells and environment

Lehti sums up the process: “The cytotoxin can change the way the cancer cells send and perceive signals and can modify the microenvironment around the cells.”

This change allows the cancer cells to withstand the damage caused by the cytotoxin—and can thus survive the chemotherapeutic attack. The researchers have found this key to the puzzle in a layer of tissue that often surrounds cancer cells.

“A fibrotic network of proteins, known as the extracellular matrix or ECM, surrounds the cancer cells, particularly the most aggressive ones,” says Lehti.

Fibrotic tissue is formed when the body tries to repair an injury. The fibrotic tissue, with the ECM network around the cancer cells, is mainly produced by normal connective tissue cells. But the cancer cells and connective tissue cells in the network can alter this tissue themselves.

“Previously, we haven’t known how the communication between the cancer cells and the extracellular matrix is affected by, or even itself influences, the development of cancer and its response to chemotherapy,” says Lehti.

But we know more about that now. Chemical and mechanical signals in the surrounding ECM tissue are already known to help cancer develop its ability to spread and to resist treatment.

“Certain signals from the ECM can critically change the cancer cells’ resistance to platinum-based cytotoxic drugs,” explains Professor Kaisa Lehti.

The cytotoxin can thus help to change both the microenvironment around the cancer cells and the ability of the cancer cells to receive and sense signals in the environment that help them to resist the cytotoxin. This can cause the cytotoxin to eventually not work.

The increased knowledge about these mechanisms is helpful when choosing treatments for people with cancer.

Featured image: Surviving ovarian cancer cells (light blue nucleus) surrounded by fibrotic tissue. Credit: Elina Pietilä, University of Helsinki

Reference: Elina A. Pietilä et al, Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance, Nature Communications (2021). DOI: 10.1038/s41467-021-24009-8

Provided by Norwegian University of Science and Technology

Medicine

Continuous Positive Airway Pressure (CPAP) Reduces Need For Invasive Ventilation in Hospitalised COVID-19 Patients (Medicine)

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  • Landmark UK trial compared three commonly used respiratory interventions to establish which works best for COVID-19 patients with acute respiratory failure.
  • Participants who received continuous positive airway pressure (CPAP) were less likely to require invasive mechanical ventilation from COVID-19.
  • Researchers found no benefit from high flow nasal oxygenation (HFNO) over standard oxygen therapy.
  • Based on this evidence, the authors say CPAP should be considered for hospitalised patients with COVID-19 needing increasing oxygen – reducing the need for invasive ventilation and relieving pressure on intensive care services.

The Respiratory Strategies in COVID-19; CPAP, High-flow, and Standard Care (RECOVERY-RS) trial has demonstrated that treating hospitalised COVID-19 patients who have acute respiratory failure with continuous positive airway pressure (CPAP) reduces the need for invasive mechanical ventilation.

Preliminary data from the trial also suggests that the routine use of high flow nasal oxygenation (HFNO), which can consume large amounts of oxygen, should be reconsidered as it did not improve outcomes for COVID-19 patients compared with conventional oxygen therapy.

RECOVERY-RS, led by the University of Warwick and Queen’s University Belfast, is the world’s largest non-invasive respiratory support trial for COVID-19 – with over 1200 participants taking part across 48 UK hospitals. The multi-centre, adaptive, randomised controlled trial compared the use of CPAP (oxygen and positive pressure delivered via a tightly fitting mask), with HFNO (high pressure oxygen delivered up the nose), against standard care (standard oxygen therapy).

All three interventions are commonly used to treat COVID-19 patients before they are moved onto invasive ventilation in a critical care bed, but it was not known which, if any, resulted in better outcomes.

Results

Over 13 months, between April 2020 and May 2021, a total of 1,272 hospitalised COVID-19 patients with acute respiratory failure, aged over the age of 18, were recruited to the study and randomly allocated to receive one of three respiratory support interventions as part of their hospital care.

380 (29.9%) participants received CPAP; 417 (32.8%) participants received HFNO; and 475 (37.3%) received conventional oxygen therapy.

The primary outcomes assessed through the trial were whether the patient went on to require tracheal intubation (invasive mechanical ventilation) or died within 30-days of beginning treatment through the trial.

In the comparison of CPAP and conventional oxygen therapy, the likelihood of patients going on to require invasive mechanical ventilation or die within 30-days of treatment was significantly lower in those who were treated with CPAP, than those who received standard care. In the CPAP group, 137 of 377 participants (36.3%) either needed mechanical ventilation or died within 30 days, compared with 158 of 356 participants (44.4%) in the conventional oxygen therapy group.

There was no difference in primary outcomes between patients in the HFNO and conventional oxygen therapy groups. In the HFNO group, 184 of 414 participants (44.4%) went on to require mechanical ventilation or die, compared with 166 of 368 participants (45.1%) in the conventional oxygen therapy group.

Based on these results, 1 person would avoid needing invasive ventilation within intensive care units (ICU) for every 12 people treated with CPAP instead of standard oxygen therapy.

Professor Gavin Perkins, Chief Investigator and Professor in Critical Care Medicine at Warwick Medical School at the University of Warwick said: “The RECOVERY-RS trial showed that CPAP was effective at reducing the need for invasive ventilation, thus reducing pressures on critical care beds. The routine use of high flow nasal oxygenation, which can consume large amounts of oxygen, should be reconsidered as it did not improve outcomes. By giving patients the most effective treatment to begin with, we can help prevent resource shortages in our NHS and make sure the right type of ventilation is available to patients when it is required.

“This is the first large trial of different types of ventilation in COVID-19. While it is encouraging that these results can help reduce the number of people who require invasive ventilation, it is important to stress that, where it is needed, invasive ventilation can be lifesaving.”

Professor Danny McAuley, Chief Investigator and Professor and Consultant in Intensive Care Medicine at the Royal Victoria Hospital and Queen’s University Belfast said: “Over the COVID pandemic, we’ve seen a large number of patients requiring high levels of oxygen and admission to ICU for invasive ventilation, causing a huge strain on staff and beds.

“The results of this trial are really encouraging as they have shown that by using CPAP, invasive ventilation may not be needed for many patients with COVID-19 requiring high oxygen levels. Avoiding invasive ventilation is not only better for the patients, but it also has important resource implications as it frees up ICU capacity. This research should help healthcare professionals in the UK and beyond manage patients with COVID-19, to improve patient outcomes while helping to lessen the burden on resources.”

Professor Jonathan Van-Tam, Deputy Chief Medical Officer said: “COVID-19 has placed huge pressure on our hospitals and intensive care units, and our doctors, nurses and all NHS staff have stepped up to meet that challenge. A key part of tackling COVID has been the improvements that staff have identified and then implemented in terms of how to best care for COVID patients.

“This study, funded by the NIHR, provides valuable evidence around how non-invasive respiratory support can be used to improve patient outcomes. Reducing invasive mechanical ventilation is better for patients and reduces pressures on mechanical ventilator capacity across the NHS.

“I want to thank the team of doctors, researchers and patient volunteers involved in today’s excellent results – hospitals across the country can now use these data to further improve care for patients and reduce the demand for mechanical ventilation as we get closer to what might still be a challenging winter period.”

Professor Lucy Chappell, Chief Scientific Adviser (CSA) for the DHSC and the National Institute for Health Research (NIHR) Chief Executive Officer, said: “Research such as this has been a huge asset to the COVID-19 response, allowing us to fine-tune our approach and improve care for patients in hospital.

“I am hugely grateful to the teams at the University of Warwick and Queen’s University Belfast for their contribution to our understanding of the virus through this NIHR-funded study, and particularly how to treat it.

“This data will help ensure hospitalised patients with COVID-19 get the best possible care, making a difference to patients and intensive care units across the country.”

Professor Nick Lemoine, Medical Director at the National Institute for Health Research (NIHR) Clinical Research Network said: “Preliminary results from this NIHR-supported trial provide important evidence which will help shape clinical practice worldwide around respiratory support interventions for hospitalised COVID-19 patients. The study will undoubtedly help improve outcomes for patients – while potentially alleviating pressure on hospital beds and critical care services.

“We sincerely want to thank everybody involved – the patients who took part in their darkest hour, and the NHS doctors and nurses who helped deliver the study right across the UK.”

Professor Simon Ball, Executive Medical Officer at University Hospitals Birmingham said: “This is an important study that will significantly influence treatment decisions. It is an example of how well NHS hospitals can deliver studies to improve clinical practice. This includes the definition of treatments that are beneficial, in this case CPAP, but just as importantly those with no apparent benefit, in this case high flow nasal oxygen. The best possible care we deliver is that focused by evidence.”

About RECOVERY-RS

Both CPAP and HFNO have been widely used worldwide in the management of COVID-19 throughout the pandemic for patients who need high levels of additional oxygen. If these treatments are not successful, patients need to be sedated and treated with a ventilator in intensive care. Although both CPAP and HFNO are commonly used in other lung conditions, prior to the RECOVERY-RS study, it was unknown how safe and effective they were for people with breathing difficulties arising from COVID-19.

The trial is led by Joint Chief Investigators Professor Gavin Perkins at the University of Warwick, and Professor Danny McAuley at Queen’s University Belfast.

It was funded and supported by the National Institute for Health Research (NIHR) as a prioritised urgent public health COVID-19 study.

RECOVERY-RS was one of the first COVID-19 studies to be classed as urgent public health research by the UK’s Chief Medical Officers in order to urgently identify strategies to reduce the need for invasive mechanical ventilation. Launched in April 2020 as COVID-19 hospitalisation began to soar, the NIHR Clinical Research Network provided prioritised support to rapidly set the study up at hospital sites across the UK and enroll participants. The NIHR’s research infrastructure, expertise and delivery support has been critical to the trial’s success.

The preliminary results of this evaluation of the data will be available as a pre-print on medRxiv on 5 August 2021 and will be submitted to a leading peer-reviewed medical journal. The results will be presented in detail at a free virtual Critical Care Reviews conference session (https://criticalcarereviews.com) on Thursday 5 August at 7.30pm.

Notes to editors:

Taking part in RECOVERY-RS: Lisa’s story

Lisa Broadhurst, 42, from Birmingham, took part in the RECOVERY-RS trial in January after contracting COVID-19.

She was rushed to hospital by ambulance on 13 January with breathing problems and dropping oxygen levels, 11 days after first experiencing symptoms of aches and pains, loss of taste and smell and a severe headache.

Diagnosed with severe COVID-19 and pneumonitis, Lisa, who is also asthmatic, said: “I’ve never been so scared in my life. I had no control of my deteriorating health. I remember Face Timing my family and letting them know how poorly I was. All I could think about was whether I’d go home or whether covid would kill me like so many other patients. The nurses would squeeze my hand and reassure me to stay strong. It was a heartbreaking time and I wouldn’t wish that feeling on anyone.”

Lisa, who received CPAP as part of the trial, remembers being connected to the machine: “The pressure of the oxygen took a little while to get used to. It was a scary experience and took my breath away at first. All I could think about was making it home to my family. I fought as hard as I could to stay alive, I cried a lot and I was scared and overwhelmed.

“But throughout the time on the machine I could see I was getting better. It was the best feeling ever leaving the hospital and walking outside into the fresh air knowing I was going home to my loved ones.”

COVID-19 still has a lasting impact on her health and her lungs are much more sensitive.

But she added: “I’m extremely grateful I took part in the trial – the level of care I received from everyone was amazing. The nurses and doctors showed so much support. I couldn’t have asked for better and taking part in the trial saved my life. I will always forever be in debt to the NHS – they helped me to go back home to my family. Research really does help benefit others and it’s the reason I’m alive today.”

Featured image credit: Unsplash

Provided by University of Warwick

Medicine

Full-dose Blood Thinners Reduce The Need For Organ Support in Moderately Ill COVID-19 Patients (Medicine)

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A large clinical trial conducted worldwide shows that treating moderately ill hospitalized COVID-19 patients with a full-dose blood thinner reduced their need for organ support, such as mechanical ventilation, and improved their chances of leaving the hospital. However, the use of this treatment strategy for critically ill COVID-19 patients requiring intensive care did not result in the same outcomes. The formal conclusions from the trial, which was supported in part by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, appear online in The New England Journal of Medicine.

“These results make for a compelling example of how important it is to stratify patients with different disease severity in clinical trials. What might help one subgroup of patients might be of no benefit, or even harmful, in another,” said NHLBI Director Gary H. Gibbons, M.D.

Researchers have observed that in some people who died from COVID-19, blood clots had formed throughout their bodies, even in their smallest blood vessels. Antithrombotics, which include blood thinners or anticoagulants, help prevent clot formation in certain diseases. Doctors did not know which antithrombotic drug, what dose, and at what point during the course of COVID-19, antithrombotics might be effective. To answer these urgent questions, three international partners came together and harmonized their trial protocols to  study the effects of using a full, or therapeutic dose, of the blood thinner heparin versus a low, or prophylactic dose, of heparin in moderately and critically ill patients hospitalized with COVID-19.

Researchers defined moderately ill patients as those hospitalized for COVID-19 without the requirement of organ support, and critically ill patients as those hospitalized for COVID-19 requiring intensive care level of support, including respiratory and/or cardiovascular organ support.

In April 2020, hospitalized COVID-19 patients received either a low or full dose of heparin for up to 14 days after enrollment. By December 2020, interim results indicated that full-dose anticoagulation did not reduce the need for organ support and may even cause harm in critically ill patients. However, one month later, interim results indicated that full doses of heparin likely benefited moderately ill patients.

“The formal conclusions from these studies suggest that initiating therapeutic anticoagulation is beneficial for moderately ill patients and once patients develop severe COVID-19, it may be too late for anticoagulation with heparin to alter the consequences of this disease,” said Judith Hochman, M.D., senior associate dean for Clinical Sciences at New York University, a corresponding author of the moderately ill study and study chair of the NIH-funded portion of the combined platform trials, Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4a) Antithrombotics Inpatient trial. “The medication evaluated in these trials is familiar to doctors around the world and is widely accessible, making the findings highly applicable to moderately ill COVID-19 patients.”

The final analysis of trial data included 1,098 critically ill and 2,219 moderately ill patients. For both moderately and critically ill patients, researchers looked at how long they were free of organ support up to 21 days after enrollment. Among moderately ill patients, researchers found that the likelihood of full-dose heparin to reduce the need for organ support compared to those who received low-dose heparin was 99%. A small number of patients experienced major bleeding, though this happened infrequently. For critically ill patients, full-dose heparin also decreased the number of major thrombotic events, but it did not reduce the need for organ support or increase their chances of leaving the hospital early after receiving treatment.

The participating partners in the multicenter trials include: Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAPexternal link) Therapeutic Anticoagulation; Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACCexternal link); and ACTIV-4a Antithrombotics Inpatient A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19. In the United States, ACTIV-4a Antithrombotics Inpatient is being led by a collaborative effort with several universities, including the University of Pittsburgh, a trial coordinating center, and New York University, the study chairs’ office and a coordinating center. ACTIV-4a Antithrombotics Inpatient is also conducting another study to test the effects of adding an anti-platelet agent to anticoagulation.

“More work needs to be done to continue to improve outcomes in patients with COVID-19,” said Matthew D. Neal, M.D., the Roberta G. Simmons Associate Professor of Surgery at the University of Pittsburgh, co-senior author of the severely ill study, co-first author of the moderately ill study, and co-chair of ACTIV-4a Antithrombotics Inpatient. “Given what we know about the type of blood clots in patients with COVID-19, testing anti-platelet agents is a particularly exciting approach.”

The collaborative trials are supported by multiple international funding organizations, including the Canadian Institutes of Health Research, the National Institute for Health Research (U.K.), the National Health and Medical Research Council (Australia), the National Institutes of Health (U.S.), and the PREPARE and RECOVER consortia (EU).

Study: Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report. DOI: 10.1056/NEJMoa2103417.

Study: Therapeutic Anticoagulation in Non-Critically Ill Patients Hospitalized for Covid-19. DOI: 10.1056/NEJMoa2105911.

ClinicalTrials.gov Identifier(s): NCT04505774; NCT04359277.

Provided by NIH/NHLBI

Medicine

Common Weight-loss Drug Successfully Targets Fat That Can Endanger Heart Health (Medicine)

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Researchers at UT Southwestern announced successful results of a clinical trial for a commonly prescribed weight-loss drug called liraglutide. In adults who are overweight or have obesity combined with high cardiovascular risk, once-daily liraglutide combined with lifestyle interventions significantly lowered two types of fat that have been associated with risk to heart health: visceral fat and ectopic fat.

“Our study used the latest imaging technology to evaluate different fat components in the body. The main finding was a significant decrease in visceral fat in patients without diabetes but who were overweight or had obesity. These results show the potential of liraglutide treatment for significantly lowering the risk of chronic disease in this population,” said Parag Joshi, M.D., preventive cardiologist, Assistant Professor of Cardiology, and senior author of the study published in The Lancet Diabetes & Endocrinology.

Visceral fat is stored within the abdominal cavity around important internal organs, such as the liver, pancreas, and intestines. Ectopic fat is stored in tissues that normally contain small amounts of fat, such as the liver, skeletal muscle, heart, and pancreas.

The 185 study participants were given a once-daily injection of liraglutide over 40 weeks of treatment. The relative effects of liraglutide on fat reduction were two-fold greater in the abdominal tissues and six-fold greater in the liver than seen on overall body weight. The treatment effect was consistent across race/ethnicity and BMI categories, and among those with or without baseline prediabetes. Liraglutide also reduced fasting blood glucose and inflammation in this trial population without diabetes, the majority of whom had normal blood sugar levels at baseline.

In a 2016 study led by UTSW investigators called the Leader trial, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes was lower in those treated with liraglutide than with placebo. “Our findings help add a possible mechanism for why there is a benefit of liraglutide on cardiovascular outcomes while also showing its benefits in people without diabetes,” said Dr. Joshi.

According to the researchers, obesity affects an estimated 1 in every 4 adults and 1 in every 5 youths, leading to substantial risk of cardiovascular disease and mortality. “Excess visceral fat and ectopic (e.g., liver) fat are central to the development of type 2 diabetes and cardiovascular disease,” said Dr. Joshi. “It remains challenging to identify those at highest risk, in order to offer them treatment in addition to lifestyle changes such as diet and exercise.”

The study was funded by an investigator-initiated grant from Novo Nordisk.

Other UT Southwestern researchers who contributed to the study include Colby R. Ayers, Bienka Lewis, Robert Oslica, Susan Rodder, and Ambarish Pandey.

UT Southwestern is nationally ranked No. 11 in Cardiology and Heart Surgery and No. 24 in Diabetes and Endocrinology in U.S. News & World Report’s 2021-22 Best Hospitals survey.

Featured image: Parag Joshi, M.D., preventive cardiologist © UT Southwestern Medical Center

Reference: Ian J Neeland et al, Effects of liraglutide on visceral and ectopic fat in adults with overweight and obesity at high cardiovascular risk: a randomised, double-blind, placebo-controlled, clinical trial, The Lancet Diabetes & Endocrinology (2021). DOI: 10.1016/S2213-8587(21)00179-0

Provided by UT Southwestern Medical Center

Medicine

Steroid Could Reduce Heavy Menstrual Bleeding (Medicine)

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Women who experience heavy menstrual bleeding could have their blood loss reduced by treatment with a common anti-inflammatory steroid, research suggests.

The study could pave the way for dexamethasone to be used as a safe, effective therapy – the first new class of treatment for heavy menstrual bleeding in nearly 20 years.

It is the first time an anti-inflammatory steroid has been trialed to treat this common health problem, which affects around one in four women in the UK and can persist for years.

The most commonly used treatment for reducing menstrual bleeding – a hormone-releasing device that is inserted into the womb cavity – is highly effective. However, nearly one fifth of new users are dissatisfied with the side effects, which include unpredictable bleeding. It is also unsuitable for women who are trying to get pregnant.

Treatment option

The trial – undertaken by a team from the University of Edinburgh – involved 107 women aged between 21 and 54 years old who had experienced heavy menstrual bleeding for time spans ranging from six months to 37 years.

The study found that women who were given a 0.9 mg dose of dexamethasone twice daily for five days showed an average reduction in menstrual blood loss volume of 19 per cent.

Researchers say the findings mean dexamethasone could be a future treatment option for women whose heavy menstrual bleeding harms their quality of life or health. It could also be used by women who experience unacceptable side-effects with hormonal treatment but do not want surgical treatment, and those who wish to try for pregnancy.

Taboo topics

Menstruation and heavy menstrual bleeding are still taboo topics and the debilitating impact of the latter is under-reported by patients. Our findings open the way for further study of dexamethasone as a possible safe and effective therapy.Hilary CritchleyProfessor of Reproductive Medicine at the University’s MRC Centre for Reproductive Health

This trial evolved from groundbreaking laboratory research and years of multi-disciplinary collaboration between clinicians and methodologists, combined with specialist expertise in new efficient and ethical approaches to trial design. It has been an exciting and gratifying journey.Dr Pamela WarnerReader in Medical Statistics at the University’s Usher Institute

This research was funded by the UK Medical Research Council and is published in the medical journal EBioMedicine.

Related links

Article published in EBioMedicine

Study medicine at the University of Edinburgh

[Satjawat Boontanataweepol via Getty Images]

Provided by Edinburgh University

Medicine

Pioneering Therapy Provides Long-term Survival For Babies Lacking Thymus (Medicine)

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An investigational treatment pioneered by a Duke Health pediatrician resulted in a one-year survival rate of 77% among children born with a rare condition in which they lack an immune system.null

The treatment, using cultured thymus tissue (CTT), has been studied at Duke since 1993 for babies born without a thymus gland, which produces the all-important T cells that are key to fighting infections.

Without treatment, babies born with the rare condition, called congenital athymia, are vulnerable to fatal infections and do not survive beyond early childhood.

“The survival rates for CTT are encouraging and give families hope that their children could live full lives,” said Louise Markert, M.D., professor in the Department of Pediatrics at Duke and lead author of a study published in the Journal of Allergy and Clinical Immunology.

Markert, a pediatric immunologist, launched the therapy in 1993 using donated thymus tissue that was otherwise routinely discarded as a byproduct of other procedures. Her initial approach involved implanting pieces of the tissue in the thigh—seeding it in well-vascularized muscle in a manner she likened to planting tulip bulbs.

Early successes demonstrated the potential for the therapy, as bone marrow stem cells navigated to the implanted thymus tissue to develop into T cells. Markert further honed the procedure over the years and the treatment now uses engineered human tissue, which is under FDA review. Enzyvant Therapeutics has licensed the technology and is seeking FDA approval; Markert and Duke have financial ties to the company.

The published analysis includes 105 patients who received the therapy over a span of more than 25 years. Ninety-five patients diagnosed with congenital athymia were included in the efficacy analysis. Of the patients who survived past one year, the survival rate was 93% at a median follow-up of 10.9 years.

Some of the surviving patients developed alopecia, autoimmune hepatitis, psoriasis, and psoriatic arthritis after the first year.

“We have demonstrated that CTT can act similarly to normal thymus tissue to produce naïve T cells that can then fight infection,” Markert said. “Our data show that cultured thymus tissue has been lifesaving for these children.”

Reference: M. Louise Markert et al, Experience with cultured thymus tissue in 105 children, Journal of Allergy and Clinical Immunology (2021). DOI: 10.1016/j.jaci.2021.06.028

Provided by Duke University School of Nursing