Tag Archives: #death

Physiology

We Cannot Cheat Ageing and Death (Physiology)

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New study finds fresh evidence for our inevitable death

A study led by Fernando Colchero, University of Southern Denmark and Susan Alberts, Duke University, North Carolina, that included researchers from 42 institutions across 14 countries, provides new insights into the aging theory “the invariant rate of ageing hypothesis”, which states that every species has a relatively fixed rate of aging.

– Human death is inevitable. No matter how many vitamins we take, how healthy our environment is or how much we exercise, we will eventually age and die, said Fernando Colchero.

He is an expert in applying statistics and mathematics to population biology and an associate professor at Department of Mathematics and Computer Science, University of Southern Denmark.

“We were able to shed light on the invariant rate of ageing hypothesis by combining an unpresented wealth of data and comparing births and deaths patterns on nine human populations with information from 30 non-human primate populations, including gorillas, chimpanzees and baboons living in the wild and in zoos” said Fernando Colchero.

In order to explore this hypothesis, the researchers analyzed the relationship between life expectancy, this is the average age at which individuals die in a population, and lifespan equality, which measures how concentrated deaths are around older ages.

Their results show that, as life expectancy increases, so does lifespan equality. So, lifespan equality is very high when most of the individuals in a population tend to die at around the same age such as observed in modern Japan or Sweden – which is around their 70s or 80s. However, in the 1800s lifespan equality was very low in those same countries, since deaths were less concentrated at old ages, resulting also in lower life expectancy.

– Life expectancy has increased dramatically and still does in many parts of the world. But this is not because we have slowed our rate of aging; the reason is that more and more infants, children and young people survive and this brings up the average life expectancy, said Fernando Colchero.

Previous research from some of the authors of the study has unraveled the striking regularity between life expectancy and lifespan equality among human populations, from pre-industrial European countries, hunter gatherers, to modern industrialize countries.

However, by exploring these patterns among our closest relatives, this study shows that this pattern might be universal among primates, while it provides unique insights into the mechanisms that produce it.

“We observe that not only humans, but also other primate species exposed to different environments, succeed in living longer by reducing infant and juvenile mortality. However, this relationship only holds if we reduce early mortality, and not by reducing the rate of ageing” said Fernando Colchero.

Using statistics and mathematics the authors show that even small changes in the rate of ageing would make a population of, say, baboons, to demographically behave as a population of chimpanzees or even humans.

‘Not all is lost’, says Fernando Colchero, ‘medical science has advanced at an unprecedented pace, so maybe science might succeed in achieving what evolution could not: to reduce the rate of ageing’.

This work was supported by NIA P01AG031719, with additional support provided by the Max Planck Institute of Demographic Research and the Duke University Population Research Institute.

Reference: “The Long Lives of Primates and the ‘Invariant Rate of Ageing’ Hypothesis,” F. Colchero, J.M. Aburto, E.A. Archie, C. Boesch, T. Breuer, F.A. Campos, A. Collins, D.A. Conde, M. Cords, C. Crockford, M.E. Thompson, L.M. Fedigan, C. Fichtel, M. Groenenberg, C. Hobaiter, P.M. Kappeler, R.R. Lawler, R.J. Lewis, Z.P. Machanda, M.L. Manguette, M.N. Muller, C. Packer, R.J. Parnell, S. Perry, A.E. Pusey, M.M. Robbins, R.M. Seyfarth, J.B. Silk, J. Staerk, T.S. Stoinski, E.J. Stokes, K.B. Strier, S.C. Strum, J. Tung, F. Villavicencio, R.M. Wittig, R.W. Wrangham, K. Zuberbühler, J.W. Vaupel, S.C. Alberts. Nature Communications, DOI: 10.1038/s41467-021-23894-3.

Provided by University of Southern Denmark

Medicine

Aspirin Use May Decrease Ventilation, ICU admission and Death in COVID-19 Patients (Medicine)

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Researchers from the George Washington University found that aspirin may have lung-protective effects and reduce the need for mechanical ventilation, ICU admission and in-hospital mortality in hospitalized COVID-19 patients

George Washington University researchers found low dose aspirin may reduce the need for mechanical ventilation, ICU admission and in-hospital mortality in hospitalized COVID-19 patients. Final results indicating the lung protective effects of aspirin were published today in Anesthesia & Analgesia. 

“As we learned about the connection between blood clots and COVID-19, we knew that aspirin – used to prevent stroke and heart attack – could be important for COVID-19 patients,” Jonathan Chow, MD, assistant professor of anesthesiology and critical care medicine and director of the Critical Care Anesthesiology Fellowship at the GW School of Medicine and Health Sciences, said. “Our research found an association between low dose aspirin and decreased severity of COVID-19 and death.” 

Over 400 patients admitted from March to July 2020 to hospitals around the United States, including those at GW Hospital, the University of Maryland Medical Center, Wake Forest Baptist Medical Center and Northeast Georgia Health System, were included in the study. After adjusting for demographics and comorbidities, aspirin use was associated with a decreased risk of mechanical ventilation (44% reduction), ICU admission (43% reduction), and in-hospital mortality (47% reduction). There were no differences in major bleeding or overt thrombosis between aspirin users and non-aspirin users. 

Preliminary findings were first published as a preprint in fall 2020. Since then, other studies have confirmed the impact aspirin can have on both preventing infection and reducing risk for severe COVID-19 and death. Chow hopes that this study leads to more research on whether a causal relationship exists between aspirin use and reduced lung injury in COVID-19 patients. 

“Aspirin is low cost, easily accessible and millions are already using it to treat their health conditions,” said Chow. “Finding this association is a huge win for those looking to reduce risk from some of the most devastating effects of COVID-19.”  

In addition to Chow, study authors include David Yamane, MD, assistant professor of emergency medicine and anesthesiology and critical care medicine at the GW School of Medicine and Health Sciences; Ivy Benjenk, RN, MPH, lead research coordinator for the Department of Anesthesiology and Critical Care Medicine at GW Hospital; and Shannon Cain, MD, third-year resident in the Department of Emergency Medicine at the GW School of Medicine and Health Sciences; as well as researchers from the University of Maryland Medical Center, Wake Forest Baptist Medical Center and Northeast Georgia Health System. 

“Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019” was published in Anesthesia & Analgesia.

Reference: Chow, Jonathan H. MD; Khanna, Ashish K. MD, FCCP, FCCM†,‡; Kethireddy, Shravan MD§; Yamane, David MD∥; Levine, Andrea MD¶; Jackson, Amanda M. MD#; McCurdy, Michael T. MD¶; Tabatabai, Ali MD¶,; Kumar, Gagan MD§; Park, Paul MD††; Benjenk, Ivy RN, MPH; Menaker, Jay MD; Ahmed, Nayab MD§§; Glidewell, Evan MD∥∥; Presutto, Elizabeth MD††; Cain, Shannon MD¶¶; Haridasa, Naeha BS; Field, Wesley MD§§; Fowler, Jacob G. BS∥∥; Trinh, Duy MD††; Johnson, Kathleen N. BS∥∥; Kaur, Aman DO§§; Lee, Amanda BS††; Sebastian, Kyle MD∥∥; Ulrich, Allison MD††; Peña, Salvador MD, PhD∥∥; Carpenter, Ross MD††; Sudhakar, Shruti MD††; Uppal, Pushpinder MD††; Fedeles, Benjamin T. MD, Capt, USAF, MC††; Sachs, Aaron MD††; Dahbour, Layth MD††; Teeter, William MD,##; Tanaka, Kenichi MD‡‡‡; Galvagno, Samuel M. DO, PhD; Herr, Daniel L. MD; Scalea, Thomas M. MD,‡‡; Mazzeffi, Michael A. MD, MPH Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019, Anesthesia & Analgesia: April 2021 – Volume 132 – Issue 4 – p 930-941
doi: 10.1213/ANE.0000000000005292

Provided by George Washington University

Medicine

Asthmatics At No Higher Risk Getting Or Dying From COVID-19, Peer-reviewed Study Shows (Medicine)

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Review of 57 studies shows people with asthma had a 14% lower risk of getting COVID-19 and were significantly less likely to be hospitalized with the virus

A new study looking at how COVID-19 affects people with asthma provides reassurance that having the condition doesn’t increase the risk of severe illness or death from the virus.

George Institute for Global Health researchers in Australia analysed data from 57 studies with an overall sample size of 587,280. Almost 350,000 people in the pool had been infected with COVID-19 from Asia, Europe, and North and South America and found they had similar proportions of asthma to the general population.

The results, published in the peer-reviewed Journal of Asthma, show that just over seven in every 100 people who tested positive for COVID-19 also had asthma, compared to just over eight in 100 in the general population having the condition. They also showed that people with asthma had a 14 percent lower risk of acquiring COVID-19 and were significantly less likely to be hospitalized with the virus.

There was no apparent difference in the risk of death from COVID-19 in people with asthma compared to those without.

Head of The Institute’s Respiratory Program, co-author Professor Christine Jenkins said that while the reasons for these findings weren’t clear, there were some possible explanations – such as some inhalers perhaps limiting the virus’ ability to attach to the lungs.

“Chemical receptors in the lungs that the virus binds to are less active in people with a particular type of asthma and some studies suggest that inhaled corticosteroids – commonly used to treat asthma – can reduce their activity even further,” she said.

“Also, initial uncertainty about the impact of asthma on COVID-19 may have caused anxiety among patients and caregivers leading them to be more vigilant about preventing infection.”

Lead author Dr Anthony Sunjaya added that while this study provides some reassurance about the risks of exposure to COVID-19 in people with asthma, doctors and researchers were still learning about the effects of the virus.

“While we showed that people with asthma do not seem to have a higher risk of infection with COVID-19 compared to those without asthma and have similar outcomes, we need further research to better understand how the virus affects those with asthma,” he said.

When the COVID-19 pandemic first spread across the world concerns were raised that people with asthma might be at a higher risk of becoming infected, or of becoming sicker or even dying.

Previous findings have shown that people with chronic respiratory conditions like asthma were reported to be at greater risk during the Middle East Respiratory Syndrome (MERS) outbreak, caused by a virus with a similar structure.

“Respiratory infections like those caused by coronaviruses can exacerbate asthma symptoms and corticosteroid treatment may increase susceptibility to COVID-19 infection and its severity,” Dr Sunjaya said.

However this study using the best evidence available on the risk of infection, severe illness – requiring admission to ICU and/or ventilator use – and death from COVID-19 in people with asthma finds “no significant difference”  of people with asthma being at higher risk.

Funded by Asthma Australia, the review included analysis of 45 hospital-based studies, six studies in the community and six with mixed setting. 22 of the studies were carried out in North America, 19 Asia, 14 Europe, and two in South America. Four of the studies only included children, making up 211 of the participants.

The average age of the participants was roughly 52; while 52.5% were males, 11.75% were current smokers and 16.2% were former. 54% had some form of comorbidities, 21% had diabetes and approximately 8% had chronic obstructive pulmonary disease.

Thirty-six studies were peer-reviewed publications; another 17 were preprints, 3 were government reports and 1 an open dataset.

The paper’s findings also show increasing age is strongly associated with an increased risk of acquiring COVID-19 among asthmatics and explained 70% of the in-between study variance in the analysis. “This is an expected finding and in line with other COVID-19 studies showing age as one of the most important predictors for vulnerability to COVID-19 and prognosis,” the authors add.

This review has “rigorously adhered to the guidelines of performing systematic reviews”, limitations, however are that this is the synthesis of primarily observational studies, with a short duration of follow-up, mainly self-reported asthma and variable reporting of outcomes which may introduce bias in the pooled effect.

Reference: Anthony P Sunjaya, Sabine M Allida, Gian Luca Di Tanna & Christine Jenkins (2021) Asthma and risk of infection, hospitalisation, ICU admission and mortality from COVID-19: Systematic review and meta-analysis, Journal of Asthma, DOI: 10.1080/02770903.2021.1888116

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Psychology

University of Limerick Research Finds New Link Between Personality and Risk of Death (Psychology)

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Ground-breaking research led by University of Limerick has revealed for the first time that the immune system directly links personality to long-term risk of death.

The study sheds new light on why people who are more conscientious tend to live longer.

Results from the new international study published in the journal Brain, Behavior, and Immunity have found that the immune system plays a previously unknown role in the link between personality traits and long-term risk of death.

“Personality is known to be associated with long-term risk of death, it is a well replicated finding observed across numerous research studies internationally,” explained Principal Investigator on the study Dr Páraic Ó Súilleabháin, from the Department of Psychology and Health Research Institute at University of Limerick.

“The critical question is ‘how’. We wanted to find out if a biological pathway such as our immune system may explain why this happens.

“Our personality is critically important throughout our lives, from early stages in our development, to the accumulation of the impact of how we think, feel, and behave across our lives, and in the years preceding our death. It is also becoming increasingly apparent how important personality actually is for our long-term health and resulting longevity. For instance, it has been shown that people scoring lower on the personality trait of conscientiousness (a tendency to be responsible, organized, and capable of self-control) can be at a 40% increased risk of future death compared to their higher scoring counterparts. What is not clear is how this could happen, and importantly, what biological pathway might be responsible for this link,” added Dr Ó Súilleabháin, a Lecturer in Psychology and Research Coordinator on the Doctoral Programme in Clinical Psychology at UL.

Led by Dr Ó Súilleabháin, this study was conducted with a team of collaborators from the Department of Psychology at UL, the Department of Psychology at West Virginia University, the Department of Psychology at Humboldt University Berlin, and the College of Medicine at Florida State University.

The researchers wanted to investigate if two biological markers which are central to the immune system may explain why personality traits are associated with long-term mortality risk. Specifically, they wanted to test if interleukin-6 and c-reactive protein which are known to play an important role in age-related morbidity may explain how our personality traits are related to how long we live. The study was drawing on data from the Midlife in the United States Longitudinal Study carried out on 957 adults who were examined over a 14-year period.

Dr Ó Súilleabháin explained: “We found that part of the reason why people who score higher on the personality trait of conscientiousness live longer is as a result of their immune system, specifically due to lower levels of a biological marker called interleukin-6. There are likely further biological mechanisms that are yet to be discovered which will give a clearer picture of all the different ways that our personalities are so critical to our long-term health.

“These findings are very important and identify for the first time that an underlying biological marker directly links personality to long-term mortality risk. With replication, these findings provide an opportunity for future interventions to increase our longevity and health across the lifespan,” Dr Ó Súilleabháin added.

Featured image: Dr Páraic Ó Súilleabháin, from the Department of Psychology and Health Research Institute at University of Limerick, who was principal investigator on the study © University of Limerick

Reference: Páraic S. O’Súilleabháin, Nicholas A. Turiano, Denis Gerstorf, Martina Luchetti, Stephen Gallagher, Amanda A. Sesker, Antonio Terracciano, Angelina R. Sutin, Personality pathways to mortality: Interleukin-6 links conscientiousness to mortality risk, Brain, Behavior, and Immunity, 2021, , ISSN 0889-1591, https://doi.org/10.1016/j.bbi.2021.01.032. (https://www.sciencedirect.com/science/article/pii/S0889159121000362)

Provided by University of Limerick

Medicine

Research Shows People with High Omega-3 Index Less Likely to Die From COVID-19 (Medicine)

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Pilot study shows positive outcomes for those suffering from COVID-19.

Researchers with the Fatty Acid Research Institute (FARI) and collaborators at Cedars-Sinai Medical Center in Los Angeles and in Orange County, CA, recently posted a report in medRχiv describing the results of a pilot study examining a possible link between low Omega-3 Index levels (lower levels of the omega-3s EPA and DHA) and risk for death from COVID-19 infection. The paper is currently undergoing peer review.

There are several papers in the medical literature hypothesizing that Omega-3 fatty acids should have beneficial effects in patients with COVID-19 infection, but to date, there are no published studies supporting that hypothesis.

This study included 100 patients admitted to the hospital with COVID-19 for whom admission blood samples had been stored. Clinical outcomes for these patients were obtained and blood was analyzed for the Omega-3 Index (O3I) at OmegaQuant Analytics (Sioux Falls, SD). Fourteen of the patients died.

The 100 patients were grouped into four quartiles according to their O3I, with 25% of the patients in each quartile. There was one death in the top quartile (i.e., 1 death out of 25 patients with O3I>5.7%), with 13 deaths in the remaining patients (i.e., 13 deaths out of 75 patients with O3I<5.7%).

In age-and-sex adjusted regression analyses, those in the highest quartile (O3I > 5.7%) were 75% less likely to die compared with those in the lower three
quartiles (p=0.07). Stated another way, the relative risk for death was about four times higher in those with a lower O3I (<5.7%) compared to those with higher levels.

“While not meeting standard statistical significance thresholds, this pilot study – along with multiple lines of evidence regarding the anti-inflammatory effects of EPA and DHA – strongly suggests that these nutritionally available marine fatty acids may help reduce risk for adverse outcomes in COVID-19 patients. Larger studies are clearly needed to confirm these preliminary findings,” said Arash Asher, MD, the lead author on this study.

Agreeing with Dr. Asher, cardiology researcher and co-developer with Dr. Harris of the Omega-3 Index, Clemens von Schacky, MD, (CEO, Omegametrix GmbH, Martinsried, Germany, and not involved with the study) said, “Asher et al have demonstrated that a low Omega-3 Index might be a powerful predictor for death from COVID-19. Although encouraging, their findings clearly need to be replicated.”

Omega-3 expert James H. O’Keefe, Jr., MD, (Director of Preventive Cardiology, Saint Luke’s Mid America Heart Institute, Kansas City, MO, and also not involved with the study) observed, “An excessive inflammatory response, referred to as a ‘cytokine storm,’ is a fundamental mediator of severe COVID-19 illness. Omega-3 fatty acids (DHA and EPA) have potent anti-inflammatory activities, and this pilot study provides suggestive evidence that these fatty acids may dampen COVID-19’s cytokine storm.”

The FARI research team is currently seeking funding to expand upon these preliminary observations. Individuals and organizations that want to support this research are encouraged to visit FARI’s donations page.

Reference: Arash Asher, Nathan L. Tintle, Michael Myers, Laura Lockshon, Heribert Bacareza, William S. Harris, “Blood omega-3 fatty acids and death from COVID-19: A Pilot Study”, medRχiv, 2021. doi: https://doi.org/10.1101/2021.01.06.21249354

Provided by Fatty Acid Research Institute (FARI)

Biology

Spitting Cobra Venoms Evolved to Cause Extreme Pain (Biology)

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Venom from spitting cobras has evolved to cause predators extreme pain as a form of self-defence, rather than for capturing prey, according to new research.

An international team including scientists from The University of Queensland, made the discovery by studying the composition of spitting cobra venoms from three groups of snakes — Asian spitting cobras, African spitting cobras and rinkhals.

Co-authors Professor Irina Vetter and Dr Sam Robinson from UQ’s Institute for Molecular Bioscience are among the team which demonstrated that the defensive mechanism had developed as a dominant genetic trait.

 “The fangs of these snakes are adapted to spray venom as far as 2.5 metres — the venom is aimed directly at the face, specifically the eyes, causing intense pain and can lead to the loss of eyesight,” Dr Robinson said.

A Mozambique spitting cobra from South Africa spits its painful venom © Wolfgang Wüster Naja.

Professor Vetter said the snakes had independently evolved the ability to spit their venoms at enemies.

“We tested how venom components affected pain-sensing nerves and showed that spitting cobra venoms are more effective at causing pain than their non-spitting counterparts,” she said.

The three different groups of venom-spitting snakes had increased production of an enzyme toxin, phospholipase-A2, which works cooperatively with other venom toxins to maximise pain.

Lead author Professor Nick Casewell from the Liverpool School of Tropical Medicine said venom spitting was ideally suited to deterring attacks from humans.

“It is intriguing to think that our ancestors may have influenced the origin of this defensive chemical weapon in snakes,” he said.

Professor Vetter and Dr Robinson are pain researchers, studying the molecular mechanisms of pain with the goal of developing new and more effective painkilling drugs.

“Pain-causing toxins from animal venoms can be useful tools to help us understand pain signalling at a molecular level, and are helping us to identify new targets for future painkillers,” Dr Robinson said.

This research was published in Science (DOI: 10.1126/science.abb9303).

Reference: T. D. Kazandjian, D. Petras, S. D. Robinson, J. van Thiel, H. W. Greene, K. Arbuckle, A. Barlow, D. A. Carter, R. M. Wouters, G. Whiteley, S. C. Wagstaff, A. S. Arias, L.-O. Albulescu, A. Plettenberg Laing, C. Hall, A. Heap, S. Penrhyn-Lowe, C. V. McCabe, S. Ainsworth, R. R. da Silva, P. C. Dorrestein, M. K. Richardson, J. M. Gutiérrez, J. J. Calvete, R. A. Harrison, I. Vetter, E. A. B. Undheim, W. Wüster, N. R. Case well, “Convergent evolution of pain-inducing defensive venom components in spitting cobras”, Science  22 Jan 2021: Vol. 371, Issue 6527, pp. 386-390 DOI: 10.1126/science.abb9303

Provided by University of Queensland Australia

Medicine

Preventing Spread of COVID-19 Earlier Saves Lives (Medicine)

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Rates of mortality from COVID-19 are lower in areas where public health measures aimed at preventing the spread of the disease were implemented earlier in the outbreak, according to a study from University of Hawaiʻi at Mānoa public health researchers. The findings are published in PLOS ONE.

© University of Hawai‘i at Manoa

For the study, researchers including Yan Yan Wu, an associate professor of biostatistics with the UH Mānoa Office of Public Health Studies, investigated data from 50 countries in Europe on COVID-19 mortality. The researchers compared the date when each country reported reaching its first 100 confirmed cases with its overall COVID-19 mortality rate.

The date of reaching 100 cases was used because it is a good indicator of the virus reaching community circulation. 

“We found that countries that reached 100 cases sooner also had higher mortality rates,” said Wu. “The European countries that experienced the earliest community circulation of COVID-19 suffered the worst consequences in terms of mortality.”

In Europe, most countries put containment measures such as closures of schools and nonessential businesses and bans on nonessential travel by mid-March 2020. Some cities were placed under lockdowns.

Timing matters

The World Health Organization first reported human-to-human transmission of the virus on January 22, 2020. For their analysis, the researchers calculated how many days it took (after January 22) for each country in Europe to reach 100 cases. They compared the countries that reached 100 cases in less than 50 days with those that took longer than 50 days.

Beyond mortality rates, the total incidence of the disease was higher and the overall life expectancy was lower in the countries that reached 100 cases in less than 50 days. Putting measures into place even a few weeks earlier could have dramatically reduced the amount of virus circulating in the community.

“We found clear evidence that timing matters,” Wu said. “Our data showed that efforts to delay the early spread of the virus may have saved an average 30 deaths daily per 1 million inhabitants.”

The findings may inform the response to the pandemic moving forward. Wu added, “The sooner measures to lower the spread of the virus are put in place, the lower the death rate.”

Wu’s coauthors include Catherine Pirkle and Tetine Sentell of the Office of Public Health Studies, and Alban and Genc Burazeri of the University of Medicine, Tirana, Albania.

Reference: Ylli A, Wu YY, Burazeri G, Pirkle C, Sentell T (2020) The lower COVID-19 related mortality and incidence rates in Eastern European countries are associated with delayed start of community circulation. PLoS ONE 15(12): e0243411. doi:10.1371/journal.pone.0243411 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243411

Provided by University of Hawai‘i at Manoa

Medicine

Rapid Blood Test Identifies COVID-19 Patients at High Risk of Severe Disease (Medicine)

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Measuring mitochondrial DNA could predict who will need ICU care, intubation.

One of the most vexing aspects of the COVID-19 pandemic is doctors’ inability to predict which newly hospitalized patients will go on to develop severe disease, including complications that require the insertion of a breathing tube, kidney dialysis or other intensive care. Knowledge of a patient’s age and underlying medical conditions can help predict such outcomes, but there are still surprises when younger, seemingly healthier patients suffer severe complications that can lead to death.

A new study from Washington University School of Medicine in St. Louis suggests that measuring mitochondrial DNA in the blood of patients with COVID-19 can help predict which patients are at highest risk of severe disease, requiring more intensive care. Mitochondrial DNA levels are a measure of tissue damage. Pictured are damaged mitochondria (dark grey areas) released from human lungs. The small dark dots surrounding the mitochondria are magnetic beads that carry antibodies used to isolate and study unhealthy mitochondria that have been released from dying tissues. © Wandy Beatty

Now, scientists at Washington University School of Medicine in St. Louis have shown that a relatively simple and rapid blood test can predict — within a day of a hospital admission — which patients with COVID-19 are at highest risk of severe complications or death.

The study, published Jan. 14 in JCI Insight, involved nearly 100 patients newly admitted to the hospital with COVID-19.

The blood test measures levels of mitochondrial DNA, a unique type of DNA molecule that normally resides inside the energy factories of cells. Mitochondrial DNA spilling out of cells and into the bloodstream is a sign that a particular type of violent cell death is taking place in the body.

“Doctors need better tools to evaluate the status of COVID-19 patients as early as possible because many of the treatments — such as monoclonal antibodies — are in short supply, and we know that some patients will get better without intensive treatments,” said co-senior author Andrew E. Gelman, PhD, the Jacqueline G. and William E. Maritz Endowed Chair in Immunology and Oncology in the Department of Surgery.

“There’s so much we still don’t understand about this disease,” he added. “In particular, we need to understand why some patients, irrespective of their ages or underlying health in some cases, go into this hyperinflammatory death spiral. Our study suggests that tissue damage may be one cause of this spiral, since the mitochondrial DNA that is released is itself an inflammatory molecule.”

The researchers said the test could serve as a way to predict disease severity as well as a tool to better design clinical trials, identifying patients who might, for example, benefit from specific investigational treatments. They also said they would like to evaluate whether the test could serve as a way to monitor the effectiveness of new therapies. Presumably, effective treatments would lower mitochondrial DNA levels.

“We will need larger trials to verify what we found in this study, but if we could determine in the first 24 hours of admission whether a patient is likely to need dialysis or intubation or medication to keep their blood pressure from dropping too low, that would change how we triage the patient, and it might change how we manage them much earlier in the disease course,” said co-senior author Hrishikesh S. Kulkarni, MD, an assistant professor of medicine.

The researchers, including co-first authors Davide Scozzi, MD, PhD, a staff scientist, and Marlene Cano, PhD, a postdoctoral research scholar, evaluated 97 patients with COVID-19 at Barnes-Jewish Hospital, measuring their mitochondrial DNA levels on the first day of their hospital stays. They found that mitochondrial DNA levels were much higher in patients who eventually were admitted to the ICU, intubated or died. The researchers found this association held independently of a patient’s age, sex and underlying health conditions.

On average, mitochondrial DNA levels were about tenfold higher in patients with COVID-19 who developed severe lung dysfunction or eventually died. Those with elevated levels were almost six times more likely to be intubated, three times more likely to be admitted to the ICU and almost twice as likely to die compared with those with lower levels.

Further, the test predicted outcomes as well as or better than existing markers of inflammation currently measured in patients hospitalized with COVID-19. Most other markers of inflammation measured in patients with COVID-19, including those still under investigation, are general markers of systemic inflammation, rather than inflammation specific to cell death, according to the researchers.

“Viruses can cause a type of tissue damage called necrosis that is a violent, inflammatory response to the infection,” Gelman said. “The cell breaks open, releasing the contents, including mitochondrial DNA, which itself drives inflammation. In COVID-19 patients, there has been anecdotal evidence of this type of cell and tissue damage in the lung, heart and kidney. We think it’s possible that measures of mitochondrial DNA in the blood may be an early sign of this type of cell death in vital organs.”

The researchers also emphasized that the test is quick and straightforward to perform in most hospital settings because it uses the same machinery that processes the standard PCR test for COVID-19. The method they developed allows mitochondrial DNA levels to be quantified directly in the blood. Without requiring intermediate steps to extract the DNA from the blood, the technique returned results in less than an hour.

Before they can apply for approval from the Food and Drug Administration (FDA), the scientists will need to verify that the test is accurate in a larger multi-center trial. They have plans to expand the research to more sites.

The study utilized samples obtained from the School of Medicine’s COVID-19 biorepository, which was developed by co-authors Jane O’Halloran, MD, PhD, an assistant professor of medicine; Charles Goss, PhD, an instructor in biostatistics; and Phillip Mudd, MD, PhD, an assistant professor of emergency medicine.

This work was supported by the Barnes Jewish Hospital Foundation; the Children’s Discovery Institute; the National Institutes of Health (NIH), grant numbers, R01HL094601, P01AI116501 and K08HL148510; and the Washington University Institute of Clinical and Translational Sciences (ICTS) COVID-19 Research Program, which is funded by the National Center for Advancing Translational Sciences (NCATS) of the NIH, grant number UL1TR002345.

Reference: Scozzi D, Cano M, et al. Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19. JCI Insight. Jan. 14, 2021. https://doi.org/10.1172/jci.insight.143299 https://insight.jci.org/articles/view/143299?utm_content=buffer269a7&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer

Provided by Washington University School of Medicine

Medicine

Stopping RAS Inhibitors Tied to Worse Outcomes in Patients With Chronic Kidney Disease (Medicine)

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Small studies have suggested that a group of medications called RAS inhibitors may be harmful in persons with advanced chronic kidney disease, and physicians therefore often stop the treatment in such patients. Researchers at Karolinska Institutet now show that although stopping the treatment is linked to a lower risk of requiring dialysis, it is also linked to a higher risk of cardiovascular events and death. The results are published in The Journal of the American Society of Nephrology.

Principal investigator Juan Jesus Carrero, professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet in Sweden. © Ulf Sirborn.

Chronic kidney disease (CKD) affects approximately ten percent of the global population. Hypertension is the most common comorbidity. Patients with CKD have an increased risk of cardiovascular disease and death.

Advanced chronic kidney disease is classified as ‘severely decreased kidney function’ and is defined as the kidney’s ability to clean the blood being less than approximately 30 percent of normal for a young adult. In some patients, CKD progresses to the point that dialysis or transplantation is required as a kidney replacement therapy to prolong life.

Renin-angiotensin system inhibitors (RAS inhibitors), including both ACE inhibitors (ending in ‘pril’) and ARBs (ending in ‘sartan’), are common medications for the treatment of hypertension, cardiovascular disease, heart failure and CKD. However, not enough is known about their efficacy and safety in patients with advanced CKD, since this population was underrepresented in the landmark randomised trials.

“Small-scale studies have suggested that stopping RAS inhibitors in these patients may improve kidney function and delay the need for kidney replacement therapy,” says Edouard Fu, MD and PhD Candidate at the Department of Clinical Epidemiology, Leiden University Medical Center and the study’s first author. “However, stopping these medications may also increase the risk of heart attacks, stroke and death. We wanted to help practitioners by evaluating the risks and benefits of this decision, and Swedish Quality Registers are uniquely suited to answer this question.”

Edouard Fu, MD and PhD Candidate at the Department of Clinical Epidemiology, Leiden University Medical Center and the study’s first author. © Royal Dutch Academy of Science.

Researchers at Karolinska Institutet and collaborators have conducted an epidemiological study using data from the Swedish Renal Registry to evaluate over 10,000 patients with advanced CKD who received RAS inhibitors over the past decade.

Comparing morbidity and mortality rates in patients whose treatment was discontinued with those who continued the drug regimen, the researchers found that discontinuing these medications was associated with an eight percent lower risk of requiring kidney replacement therapy.

However, discontinuing was also linked to a thirteen percent higher risk of death at five years, and a twelve percent higher risk of suffering a heart attack or stroke.

“The use of RAS inhibitors in patients with advanced CKD is controversial, and many doctors deprescribe them,” says principal investigator Juan Jesus Carrero, professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet in Sweden. “Rather than routinely discontinuing treatment, our results show that the issue is a complex one and that doctors must carefully weigh the protective effects of RAS inhibitors on the cardiovascular system against the potential harms on the kidneys. Until clinical trials are performed, this evidence supports continued use of this lifesaving therapy in patients with advanced CKD who are doing well on the medications.”

He points out that sometimes these medications may have to be stopped for other reasons, for example, if patients have persistently high blood potassium levels that don’t respond to management.

The study was conducted in collaboration with Leiden University Medical Center (the Netherlands), McMaster University (Canada) and the London School of Hygiene and Tropical Medicine (UK). It was supported by grants from the Swedish Research Council, the Swedish Heart and Lung Foundation, and the Westman Foundation. Some of the authors receive funding and honoraria from pharmaceutical companies for issues unrelated to this study; the scientific paper lists potential conflicts of interest in full.

Reference: Edouard L. Fu, Marie Evans, Catherine M. Clase, Laurie A. Tomlinson, Merel van Diepen, Friedo W. Dekker and Juan J. Carrero, “Stopping Renin-Angiotensin System Inhibitors in Patients with Advanced CKD and Risk of Adverse Outcomes: A Nationwide Study”, JASN December 2020, ASN.2020050682; DOI: https://doi.org/10.1681/ASN.2020050682 https://jasn.asnjournals.org/content/early/2020/12/27/ASN.2020050682

Provided by Karolinska Institute