Blood pressure medications decrease death and severe disease in COVID-19 patients

At the start of the pandemic, there was concern that certain drugs for high blood pressure might be linked with worse outcomes for COVID-19 patients.

Because of how the drugs work, it was feared they would make it easier for the coronavirus to get inside the body’s cells. Nevertheless, many national medical societies advised patients to continue taking their medication.

With the potential for a second wave, it was essential to investigate whether patients could safely continue using these drugs. So, our team at the University of East Anglia set out to discover what effect they have on the progress of COVID-19.

Instead of putting patients at risk, we found that these medications actually lower the risk of death and severe disease in COVID-19 patients.

Bad outcomes cut by one-third

We pooled data from 19 relevant COVID-19 studies that included patients taking two particular types of blood pressure medication: angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). This allowed us to look at the outcomes of more than 28,000 COVID-19 patients to assess the effects of these drugs.

ACEIs and ARBs work by acting on the renin-angiotensin-aldosterone system (RAAS), which is essential for regulating blood pressure and the balance of fluids and electrolytes. These drugs were also thought to potentially increase the expression of a protein found on the surface of cells called angiotensin-converting enzyme 2 (ACE2).

Apart from helping regulate blood pressure, the ACE2 protein is also what allows the coronavirus to enter the body’s cells. This is why there were concerns about patients using these drugs. If the medications increased the amount of ACE2 present on cells, it was suspected they would make it easier for the virus to infect them, worsening a patient’s condition.

But when we looked at the outcomes of patients taking ACEIs and ARBs compared with those not on these medications, this wasn’t the case.

We found no evidence that these medications might increase the severity of COVID-19 or the risk of death. On the contrary, among patients taking ACEIs and ARBs that had been prescribed to treat high blood pressure, there was actually a significantly lower risk of death, being admitted to intensive care or being put on ventilation. We observed a reduction of such events by one-third in this group.

It may be that these medications actually have a protective role—particularly in patients with high blood pressure.

What’s behind this effect?

It’s not clear why patients taking ACEIs and ARBs experienced less severe disease, but there are a couple of points to consider.

The first is that while theoretically these drugs were thought to increase ACE2 levels, there’s no convincing evidence that this actually happens. We don’t have any clinical data on the effects of these drugs on ACE2 expression in human tissue.

And even if these drugs do increase ACE2 levels in cells, not all of it is surface-bound. Additional ACE2 that appears elsewhere in the cell might not function as an entry point for SARS-CoV-2.

There’s also a second potentially relevant piece of information. Infection with SARS-CoV-2 may also lead to an overreaction of the RAAS pathway – which is what these blood pressure drugs target—and inflammation. This increased inflammatory process is thought to be the culprit for acute lung injury and can lead to worsening pneumonia and acute respiratory distress syndrome. Hence, it might be that taking medications that inhibit the RAAS system prevents such a sequence of events and improves clinical outcomes in COVID-19.

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Biomarker reveals how aggressive biliary tract cancer is in patients

The cancer called biliary tract cancer (BTC) is not the most widespread form of cancer. In western countries, about 1.6 in 100.000 gets the diagnose every year. It is, however, a very aggressive form of cancer.

The majority of patients with BTC are diagnosed with advanced disease and has an average survival of only 1 year from initiation of chemotherapy. With such narrow survival windows, it is crucial to improve our understanding of the disease.

Now, researchers from Biotech Research & Innovation Centre at the University of Copenhagen and Herlev and Gentofte Hospital along with collaborators from Rigshospitalet and Sygehus Lillebaelt have identified a biomarker that can tell doctors how aggressive a patient’s disease may be.

“We have found a biomarker that reliably predicts how aggressive a patients disease will evolve, which in the future could help doctors in the hospitals make the right decisions about chemotherapy for the benefit of each BTC patient,” says Jesper Andersen, Associate Professor at BRIC.

Biomarkers can used for more than the diagnosis

The researchers measured the levels of two inflammatory proteins and a biomarker commonly used in pancreatic cancer before and during chemotherapy in patients with advanced BTC and found that patients with higher levels of these markers before chemotherapy had a lower survival rate. Especially one protein called IL6 (interleukin-6) proved to be superior to the other markers in predicting those patients at greatest risk of death.

“A common misperception may be that biomarkers are mainly needed to diagnose a specific cancer type, but diverse biomarkers are also needed to guide clinical decision-making throughout each patients’ individual journey. These types of prognostic and predictive biomarkers deserve increased attention, in particular as they are playing important roles in the increasingly individualized management of more common cancer types”, says Jesper Andersen.

There are several markers to predict patients at greatest risk of death, however it was confirmed that the prognostic information provided by measuring IL-6 is not captured by other inflammatory markers already in routine clinical use. For instance, about 10 percent of the population does not express the marker that is normally measured (CA19-9) to predict the patient clinical outcome. Therefore, the course of disease cannot be predicted for these patients using CA19-9, for which IL-6 may be used instead.

Inhibiting IL-6 may improve response to chemotherapy

By inhibiting signaling of the protein IL-6 in a mouse model of human BTC, researchers discovered that the response of mouse tumors to chemotherapy significantly increased.

“Our data suggests that inhibiting IL-6 signaling may extend therapeutic benefit compared to chemotherapy alone. However, this will require careful evaluation in randomized clinical trial settings. Such a trial is currently ongoing at Herlev and Gentofte Hospital and results from this and potential future trials will contribute to our knowledge in regards to the potential of targeting the IL-6 pathway in patients with BTC”, says Jesper Andersen

Large sample size made possible through collaboration

Researchers studying BTC face a data-challenge since only 1.6 per 100,000 of Western populations are diagnosed with BTC annually. This makes it difficult to collect comprehensive amounts of patient data. Therefore, one of the key strengths of this study lies in the patient numbers attained and analyzed in this rare cancer demographic, amounting to 1590 serum samples from 452 patients with advanced BTC.

Furthermore, the study explores advanced BTC patients who represent the majority of patients at diagnosis, while the majority of previous BTC studies published to date have focused on early stage disease.

“It is imperative to increase representation of these patients with the worst prognosis in subsequent studies. These studies should also include longitudinal sampling throughout the patient’s clinical history, as we have done here”, says Jesper Andersen, group leader at BRIC.

The sample size achieved in this study was only made possible through the comprehensive collaboration between Herlev and Gentofte Hospital, Rigshospitalet and Sygehus Lillebaelt in Denmark.

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Study shows liver injury is common and prognostic in COVID-19 patients

Researchers from the Faculty of Medicine at The Chinese University of Hong Kong (CU Medicine) have recently conducted a study to investigate the impact of liver injury on clinical outcomes in COVID-19 patients. Data from over 1,000 COVID-19 patients in Hong Kong was analysed and liver injury was found in around 20% of the patients. The estimated risk of COVID-19 patients with liver injury experiencing adverse clinical outcomes such as intensive care unit (ICU) admission, use of invasive mechanical ventilation or death was almost eight times of other patients. It is suggested that liver function monitoring is important regarding its association with adverse clinical outcomes in COVID-19 patients. These findings have been published recently in the world-renowned medical journal Gut. In view of the high prevalence of various chronic liver diseases in the Asia-Pacific region, CU Medicine’s researchers led a group of experts from Mainland China, Japan, Singapore and Australia to issue a position statement on the management of COVID-19 patients with liver derangement. The statement has been published recently in another international medical journal The Lancet Gastroenterology & Hepatology.

About 20% of COVID-19 patients in Hong Kong were found to have liver injury

Liver injury, in the form of hepatitis, cholestasis or both, can be observed in patients infected by different coronaviruses. For the territory-wide study in Gut, researchers from CU Medicine analysed the data from 1,040 COVID-19 patients in Hong Kong. It was found that the level of liver enzyme alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was elevated in 23% of the COVID-19 patients, which indicated liver damage.

An association between liver injury and the chance of adverse clinical outcomes was also identified. Overall, 53 (5.1%) were admitted to ICU, 22 (2.1%) received invasive mechanical ventilation, and 4 (0.4%) died. Among them, 71% had liver injury. The analysis indicated that the estimated risk of patients with liver injury having adverse clinical outcomes is eight times of others.

First author of the study, Dr. Terry Cheuk Fung YIP, post-doctoral fellow of the Department of Medicine and Therapeutics at CU Medicine, explained, “Our study shows that liver injury was common in COVID-19 patients. Although the exact impact of the novel virus on the liver has not been well elucidated so far, our findings proved that the chance of patients with liver injury having adverse clinical outcomes is obviously higher than that of others. This shows that liver injury is prognostically significant in COVID-19 patients.”

Professor Grace Lai Hung WONG, Professor, Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics at CU Medicine, added, “Liver injury is possibly caused by systemic inflammation and adverse drug reactions in severe COVID-19 patients who have been receiving different medical treatments. As the degree of liver injury could be impacted by coexisting chronic hepatitis in patients, a thorough review of medical history and detailed investigation for concomitant liver diseases are crucial to improve patient outcomes.”

Furthermore, cautious use of appropriate medications with least hepatotoxicity as well as vigilant monitoring of liver biochemistries are recommended in order to minimise liver injury in COVID-19 patients.

As the pandemic continues and CU Medicine’s study has proved that the risk of adverse clinical outcomes in COVID-19 patients is closely related to liver health, it would be clinically helpful to provide practice recommendations for various common clinical scenarios of liver derangement, especially in the Asia-Pacific region where the prevalence of liver diseases is the highest worldwide. According to the World Health Organization, liver diseases caused 4.6% of deaths in the Asia-Pacific region in 2015, compared with 2.7% in the U.S. and 2.1% in Europe.

In response to this utmost need, the Asia-Pacific Working Group for Liver Derangement, led by the hepatologists from CU Medicine, published an Asia-Pacific position statement in June this year on the management of COVID-19 patients who have been or are at risk of developing liver derangement. Clinical scenarios covered in the statement included the precautions for the use of pharmacological treatment for COVID-19 in patients with liver derangement, for example liver test should be conducted twice weekly in patients on potentially hepatotoxic medication, those with pre-existent liver disease, and more frequently in any patients with abnormal liver function.

The statement also proposed the assessment and management of patients with hepatitis B or hepatitis, non-alcoholic fatty liver disease, liver cirrhosis, and liver transplantation during the pandemic.

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Ethical recommendations for triage of COVID-19 patients

An international expert group led by Mathias Wirth, professor of systematic theology and ethics at the University of Bern, has developed recommendations for avoiding triage of COVID-19 patients in extreme situations. The recommendations should support medical personnel in difficult decisions during a second wave of the infection and ensure better patient care.

“A lack of intensive care ventilation units owing to rapidly increasing infection rates numbers among the most significant nightmare scenarios of the corona pandemic,” says Mathias Wirth, head of the Ethics Department in the Faculty of Theology at the University of Bern, because: “Shortages of supply can result in triage of patients suffering from severe cases of COVID-19 and thus force a life or death decision.” Here, triage means favoring some COVID-19 patients over others depending on urgency and prognosis. Together with experts from Yale University, King’s College London, Charité Berlin and Essen University Hospital, medical ethicist Mathias Wirth has prepared a statement on these difficult decisions. The statement was published in the American Journal of Bioethics (AJOB), the most frequently cited scientific journal in the entire field of ethics.

Triage is only ethically justifiable under very specific circumstances

The experts warn against the possibility of prematurely implementing triage; even though triage allows for decisions based on fairness in extreme situations, it leads to significant strain on the affected parties, relatives and medical personnel. In order to avoid it, every effort must be made to transfer seriously ill patients to other hospitals without shortages of supply—across country borders in case of emergency, according to the authors.

In concrete terms, Mathias Wirth’s team of researchers recommend increased regional, national and even international collaboration in intensive care for COVID-19 patients in preparation for future waves of infection. “Just because triage is correct under some circumstances does not mean that it is correct under all circumstances,” says Wirth. “There is no real and legitimate triage situation as long as treatment spaces are available elsewhere.”

Negative decision requires special care

Secondly, a negative triage decision for individual people should not under any circumstances mean that their medical and psychological care is neglected. Quite the opposite: If they are deprived of a ventilator, maximum effort is required for their care and treatment, both for them and for their relatives.

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Kidney problems more prevalent in NYC COVID-19 patients

Hospitalized COVID-19 patients at a New York City medical facility had higher rates of kidney complications than other COVID-19 patient groups in different areas of the U.S. and other countries, according to a new study from researchers at Columbia University Irving Medical Center and NewYork-Presbyterian.

The study, using data from electronic health records and published recently in the British Medical Journal, also found the need for mechanical ventilation was greatest at two different points after symptom onset.

The study offers a detailed look at the clinical course of the first 1,000 COVID-19 patients treated at NewYork-Presbyterian/Columbia University Irving Medical Center between March 1 and April 5, 2020.

Patients in the study had higher rates of underlying chronic conditions than reported in other patient populations; the most common were hypertension (60%) and diabetes (37%). More than half of patients hospitalized for COVID-19 were male, and the median age was 63.

Nearly 34% of the patients admitted for COVID-19 developed acute kidney injury, versus 15% of patients in a recent report from China and 19% of patients in a report from Washington State. Almost 80% of patients in the ICU developed acute kidney injury.

The researchers also found that more than 95% of patients who were intubated required mechanical ventilation within the first 14 days, at either 3-4 days or 9 days after symptom onset.

“The finding that there were two points in time to intubation for critically ill COVID-19 patients tells us when we might need to be most vigilant,” says George Hripcsak, MD, MS, chair and Vivian Beaumont Allen Professor of Biomedical Informatics at Columbia University Vagelos College of Physicians and Surgeons and co-corresponding author of the study. “Knowing that intubation is much less likely to be needed after 15 days can help clinicians decide if it is safe for a patient to return home.” Dr. Hripcsak is also director of medical informatics services for NewYork-Presbyterian/Columbia University Irving Medical Center.

The median length of stay for COVID-19 patients in the current study was 6 days, similar to that of patients in a recent report from China. However, in the current study patients in the ICU had a median hospital stay of 23 days, compared with 8 days for critically ill patients in the Chinese study. More than a third of the critically ill patients remained hospitalized at the end of the study.

“Our study provides valuable details about the clinical course of hospitalized COVID-19 patients from one of the largest epicenters of the pandemic,” says RuiJun Chen, MD, a postdoctoral research fellow in biomedical informatics at Columbia University Irving Medical Center, clinical assistant professor of medicine at Weill Cornell Medicine, and co-corresponding author of the study. “As the pandemic continues to spread around the globe, our findings may have implications for planning and resource allocation to accommodate the needs of critically ill patients, and for de-escalation of care, rehabilitation, and follow-up care after prolonged stays on a ventilator or in the ICU.”

The overall mortality rate, around 21%, was similar to other patient cohorts. The mortality rate among ICU patients was 43.6%.

“Describing our COVID-19 patient population is the first step toward identifying important risk factors for experiencing severe disease,” says Hripcsak. “Additional studies are needed to tease out what is actually causing the differences we saw in our population versus other populations.”

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Study shows patients with hemorrhagic brain disease have disordered gut microbiomes

A new study shows that people with a rare genetic disease that causes bleeding in the brain have gut microbiomes distinct from those without the disease. Moreover, it is the molecules produced by this bacterial imbalance that cause lesions to form in the brains of these patients.

The results are the first in any human neurovascular disease. They have implications both for treating the disease and in examining other neurovascular diseases that could be affected by a person’s gut microbiome.

The study was led by investigators at University of Chicago Medicine and published May 27 in Nature Communications. It examined the gut bacteria of patients with cavernous angioma (CA), a disease where blood vessel abnormalities develop in the brain and cause strokes, seizures and serious neurologic complications. The disease is caused by a genetic mutation in the lesion —which may be inherited or occurs sporadically—and its severity and course vary widely among patients.

UChicago is a leader in studying this disease. It has been designated as a cavernous angioma center of excellence and treats patients with the condition from all over the world.

Investigators had hints that the disease could be affected by the gut microbiome: Senior author Issam Awad, MD, the John Harper Seeley Professor of Neurosurgery and Director of Neurovascular Surgery at UChicago Medicine, was a partner in a previous study in mice, which showed that the cells that lined the blood vessels of the brain reacted to the animals’ gut bacteria.

“The implications of that were very big,” he said. “But we didn’t know if this concept of a unique microbiome that favors the development of lesions would be true in human beings.”

To find out, UChicago researchers—working with investigators at the University of California San Francisco, University of New Mexico, University of Pennsylvania, and the Angioma Alliance patient support group—collected stool samples from more than 120 CA patients.

The samples were then analyzed for their bacterial content and compared with samples from the general population. The CA samples showed significantly higher amounts of gram-negative bacteria and less gram-positive bacteria. The researchers identified a combination of three common bacterial species, whose relative abundance can distinguish CA patients from control patients without CA lesions, with high sensitivity and specificity.

The CA samples also showed an imbalanced network of bacteria that was much more disordered than the general population’s bacterial network. “The CA patients from all the different collection sites had the same distinctive microbiome, regardless of whether they had inherited the mutation or had a sporadic lesion, and regardless of the number of lesions they had,” Awad said. The investigators further showed that the bacterial imbalance in patients with CA produces lipopolysaccharide (LPS) molecules, which travel through the bloodstream to the brain and attach to the brain’s blood vessel lining, facilitating lesion development. “All this evidence pointed to the microbiome as a cause of lesions rather than an effect,” Awad said.

The investigators also collected blood from several CA patients and used advanced computational machine learning to identify the combination of molecular signals associated with the disease. Those with CA had significantly different LPS-related related blood biomarkers and inflammatory molecules. The result was essentially a smart, personalized test for each CA patient. “By looking at both bacteria combinations and the blood biomarkers, we were able to measure just how aggressive the disease was in each patient,” said Sean Polster, MD, a neurosurgery resident at UChicago Medicine and first author on the paper. Polster spent two years of his neurosurgery residency coordinating the study among the different institutions.

The researchers are beginning to think about how these results affect treatment. Earlier studies in mice showed that those fed emulsifiers—which are often used as preservatives in processed foods—had more bleeding in the brain, likely due to the way they disrupted the gut’s bacterial network. The researchers now tell patients to avoid these preservatives.

Though antibiotics and probiotics might seem like natural courses of treatment, they could change the bacterial balance in ways that lead to bigger problems. “This is more complicated than it appears,” said Awad. However, he tells CA patients who have infections caused by gram-negative bacteria (such as urinary tract infections or prostatitis) to have them treated right away to avoid more potential brain lesions.

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Architect designs ‘healthier’ temporary ICUs for COVID-19 patients

They went from a conversation on a Thursday morning to blueprints on Monday and a full-scale prototype built five days later. University of Toronto alumnus Tye Farrow, who graduated with a degree in architecture in 1987, and friend Ray Arbesman moved quickly to design temporary intensive care units in response to the COVID-19 pandemic.

Farrow, who is the senior partner at Farrow Partners Inc. and the current president of the U of T Alumni Association, is known for creating buildings that wrap health-promoting features into their design. Arbesman is the founder of Nucap Industries, a global technology company, and the inventor of a novel mechanical system that can bind building materials together.

Together, they’ve developed Solace Rapid Assembly—High Performance COVID-19 Inpatient Bed Solutions, and they’re hoping the project could soon help hospitals around the world that are struggling to care for COVID-19 patients.

“Our goal has been to create solutions that are faster, cheaper, smarter, safer, more adaptable to individual hospital needs and importantly—healthier,” says Farrow.

Farrow founded the Cause Health movement to promote designs that nurture complete wellness, incorporating environmental sustainability, cultural sensitivity, a sense of purpose and health-boosting features such as natural materials, fractal shapes, and sunlight.

For example, Farrow designed the Credit Valley Cancer Centre in Mississauga with tree-like structures that evoke a person reaching to the sky.

“Spaces can tune basic emotions and background bodily feelings from negative to positive,” says Farrow. “Neurophysiologists call the principle ‘neural mirroring’ – we model, or feel into, feelings we observe in another person.”

He adds that a building environment creates a similar response, so the reaching structures in the Mississauga hospital seek to generate optimism, as well as a sense of life and growth, and an uplifting feeling that you are somewhere special and purposeful.

Farrow is currently earning a master’s degree in neuroscience applied to architecture and design—a field so specialized “I believe I will be the only architect in Canada with this degree,” he says.

“There is scientific evidence that space can be an accelerant or leave us numb. And the human dimension connecting space and performance for medical staff and patients alike is at the top of my mind.”

Farrow’s design for the ICU structures is based on an innovative, never-before used building technique: wood blocks laminated with metal instead of glue. Arbesman, a U of T donor, initially invented the fail-safe, velcro-like technology to build safer car brake pads, but began collaborating with Farrow on possible construction uses about five years ago.

The resulting blocks are as strong as concrete, but lighter and as easy to assemble as Lego. Even unskilled volunteers could build one of the 12-bed ICU units on a parking lot or vacant lot in a few hours, according to Farrow.

Features such as clerestory windows to introduce natural light are designed to lower patient and staff stress, while the unit’s wraparound logistics corridor is environmentally controlled so that workers who service mechanics, electricity and medical gases remain isolated from patient areas.

Farrow was inspired to improve on other temporary hospital solutions he’d seen on the news. “The environments we build to support our medical staff and patients need to be the meal equivalent to a fruit-, vegetable- and protein-enhanced energy drink smoothie,” he says, “giving you mental energy and clarity, physical strength and resiliency and mind comfort; an accelerant that will help you succeed under stressed conditions.”

Solace launched on April 23. “We already have interest from a range of different organizations in Canada, the U.S. and Israel,” says Farrow. “People are looking at it for the COVID-19 ICU responses, but because it is permanent in character, yet can also be disassembled easily, jurisdictions are also looking at it for other related uses that will need a longer shelf-life solution as we move into the winter.”

“I thought that the grip timber block solution was perfect as it could give a rapid response solution that could be designed to any medical special need, versus a fixed size as with shipping container structures,” he says. “And we can create an enhanced environment for staff and patients alike.

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