Tag: sepsis

Categories : COVID Diseases, Syndromes and ConditionsTags :

Macrophage Discovery Could Lead to Treatments for Diseases Such as Lupus and COVID

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A macrophage engulfing a yeast cell. Source: CC0

Scientistshave made an important breakthrough in understanding failures during the progression of inflammatory diseases and in doing so unearthed a potential new therapeutic target. The scientists report in Nature that an enzyme called Fumarate Hydratase is repressed in macrophages. These immune cells are already implicated in a range of diseases including Lupus, arthritis, sepsis and COVID.

Lead author Luke O’Neill, Professor of Biochemistry at Trinity said: “No-one has made a link from Fumarate Hydratase to inflammatory macrophages before and we feel that this process might be targetable to treat debilitating diseases like Lupus, which is a nasty autoimmune disease that damages several parts of the body including the skin, kidneys and joints.”

Joint first-author Christian Peace added: “We have made an important link between Fumarate Hydratase and immune proteins called cytokines that mediate inflammatory diseases. We found that when Fumarate Hydratase is repressed, RNA is released from mitochondria which can bind to key proteins ‘MDA5’ and ‘TLR7’ and trigger the release of cytokines, thereby worsening inflammation. This process could potentially be targeted therapeutically.”

Fumarate Hydratase was shown to be repressed in a model of sepsis, an often-fatal systemic inflammatory condition that can happen during bacterial and viral infections. Similarly, in blood samples from patients with Lupus, Fumarate Hydratase was dramatically decreased.

“Restoring Fumarate Hydratase in these diseases or targeting MDA5 or TLR7 therefore presents an exciting prospect for badly needed new anti-inflammatory therapies,” said Prof O’Neill.

Excitingly, this newly published work is accompanied by another publication by a group led by Professor Christian Frezza, now at the University of Cologne, and Dr Julien Prudent at the MRC Mitochondrial Biology Unit (MBU), who have made similar findings in the context of kidney cancer.

“Because the system can go wrong in certain types of cancer, the scope of any potential therapeutic target could be widened beyond inflammation,” added Prof O’Neill.

Source: Trinity College Dublin

Categories : Antibiotics HospitalsTags :

Antibiotic Stewardship and Sepsis Management: Achieving the Best of Both

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Photo by Anna Shvets on Pexels

Lessening sepsis’s deadly effects means quickly recognising its signs and symptoms, and initiating antibiotic treatments, but some experts have wondered whether this may contribute to antibiotic overuse, especially with time-to-treatment performance measures. A new study published in JAMA Internal Medicine showed that it was possible to effectively treat sepsis while engaging in antibiotic stewardship.

The study led by Hallie Prescott, MD, of the University of Michigan Health Division of Pulmonary and Critical Care and Vincent Liu, MD, of Kaiser Permanente Division of Research, looked at data from more than 1.5 million patients from 2013–2018. Patients included came to the emergency department with signs of systemic inflammatory response syndrome (SIRS), which includes increased heart rate, abnormal body temperature, among other signs.

The research team analysed antibiotics use in these patients, including number receiving antibiotics, when treatment started, treatment duration medications and the broadness of spectrum of the antibiotics.

“We showed in the overall cohort, that antibiotic use decreased. There was a slight decrease in the proportion treated within 48 hours, a more impressive decrease in the average number of days of antibiotic treatment, and also a decrease in the use of broad-spectrum antibiotics,” said Dr Prescott.

About half of the people who met the criteria for SIRS received antibiotics within 12 to 48 hours after admission, a practice that decreased slightly over time. At the same time, 30-day mortality, length of hospitalisation, and the development of multi-drug resistant bacteria also decreased.

“This study adds to our national conversation about how to combat sepsis most effectively. It also confirms that we now need to look for new opportunities to mitigate sepsis by finding patients at high risk before they arrive at the hospital, identifying hospitalised patients most likely to benefit from specific treatments, and enhancing their recovery after they survive sepsis,” said Dr Liu.

Dr Prescott agrees: “The pushback has been [time-to-treatment for sepsis] should not be a performance measure because it’s going to cause more harm than good, and I think our data shows it probably does more good than harm. We have shown that 152 hospitals have been able to make improvements in stewardship and sepsis treatment at the same time, contrary to popular belief.”

Source: Michigan Medicine – University of Michigan

Categories : AntibioticsTags :

Nanoparticle Could Boost Polymyxin B for Gram-negative Sepsis

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Patient's hand with IV drip
Photo by Anna Shvets on Pexels

To treat Gram-negative sepsis, Purdue University researchers are developing an injectable nanoparticle that can safely deliver Polymyxin B at high enough levels to inactivate endotoxins. Their research is published in Science Advances.

With an estimated annual mortality of between 30 and 50 deaths per 100 000 population,this condition ranks in the top 10 causes of death. One in three patients who die in a hospital has sepsis. Sepsis is a systemic illness caused by microbial invasion of normally sterile parts of the body, occurring when the body’s immune response to an infection or injury goes unchecked. The condition makes blood vessels leaky, leading to inflammation and blood clots, leading to impaired blood flow and possible death.

Professor Yoon Yeo leads a Purdue University team developing biocompatible nanoparticles that treat sepsis systemically through intravenous injection.

Prof Yeo said Polymyxin B, a traditional antibiotic, can inactivate endotoxins that cause a specific type of sepsis, but it may be too toxic for systemic application. For sepsis therapy, it mostly has been tested in extracorporeal blood cleaning, which is cumbersome and time consuming.

“Our nanoparticle formulations reduce dose-limiting toxicity of Polymyxin B without losing its ability to inactivate endotoxins,” Prof Yeo said.

In mouse models of sepsis, 100% treated with the Purdue nanoparticle were protected from excessive inflammation and survived.

“This technology holds promise as a safe, convenient option for patients and physicians,” Prof Yeo said.

Source: Purdue University

Categories : Ethics and Law Medical Research & TechnologyTags :

Controversial Vitamin C Sepsis Trial Faked?

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Patient's hand with IV drip
Photo by Anna Shvets on Pexels

The data underpinning a controversial study of the use as vitamin C as a sepsis treatment may in fact be fraudulent, according to an analysis by an Australian physician and statistician, reports MedPage Today.

PhD student Kyle Sheldrick, MBBS, alleges that the pre- and post- comparison groups involved in the 94-patient study were too similar to be realistic.

In an interview with MedPage Today, Sheldrick said the case is “extreme”, stating that “This is probably the most obviously fake data I have seen. … These groups are more similar than would be probable.”

The paper, led by Paul Marik, MD – who led another COVID protocol study that has since been retracted – has been the subject of much debate in the intensive care community since it was published in 2017. The so-called HAT protocol was a simple regimen of hydrocortisone, ascorbic acid (vitamin C), and thiamine which could have saved many lives easily if it indeed worked. Obviously, there was much excitement worldwide about the significance of the findings – but not all were convinced.

“The effect size seemed just impossible,” said Nick Mark, MD, an ICU physician at Swedish Medical Center. “It seemed too good to be true.”

The trial was followed by larger studies, and so far none have shown shown a similar reduction in mortality, raising suspicions even further, Dr Mark said. With Sheldrick’s analysis, the penny dropped: “This was under our noses for 5 years,” Mark said. “This isn’t just a mistake. We know things can be done unethically, but to actually fake it? That it’s not just flawed, but perhaps actually fraudulent?”

Sheldrick told MedPage Today the key problem with the Marik paper is “probably the most common sign of fraud that we see, which is overly similar groups at baseline.” That is, people tend to fake data which do not vary enough from the average.

Sheldrick said he first looked at the study methods, which noted a pre- and post- comparison design, rather than a randomised or matched case-control design. With such a design, one would expect a more random distribution of baseline characteristics, but that wasn’t the case for the Marik paper, he said.

A further analysis with Fisher’s test showed that most P-values were 1, meaning they were distributed perfectly evenly across two time periods – and only one fell below 0.5. Instead, an even spread should be expected with an overall value of 0.5.

Sheldrick sent his findings to the journal CHEST and to Marik’s former employer Sentara Norfolk General Hospital, but had not heard back from either.

While Sentara Norfolk General Hospital did not respond to comment, and the journal CHEST could not confirm whether an investigation was underway but that it did take ethical concerns very seriously.

A spokesperson for Dr Marik emailed a statement to MedPage Today, claiming that the conclusions had been validated in several meta-analyses, and recommended the source examine “this and other research on the data before making false allegations on social media. Such claims are harmful and do not add to the public discourse.”

This wouldn’t be the first time concerns have been raised about data in a paper that Dr Marik co-authored. In November 2021, the Journal of Intensive Care Medicine (JICM) retracted an article by Marik and others on their MATH+ protocol for COVID. The retraction followed a communication that raised concerns about the accuracy of COVID mortality data from the hospital used in the article.

“It seems a bit improbable for someone to discover two miracle cures in three years,” Dr Mark commented to MedPage Today.

Dr Mark noted that the 2017 paper is widely cited, and even if the intervention was not directly harmful, the resources invested in subsequent large, high-quality trials of vitamin C and sepsis could have been better spent.

“While I’m really glad we did high-quality studies and had brilliant people working on this, it’s kind of a shame,” he said. “Instead of studying vitamin C based on a faulty premise, we could have spent our efforts elsewhere.”

Source: MedPage Today

Categories : Lab Tests and ImagingTags :

New Biosensor Rapidly Measures ATP and Lactate in Blood Samples

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The prototype of the ATP and lactate sensor developed in the study (left); and the integrated sensor chip that detects ATP and lactate levels (right). Credit: Akihiko Ishida, Hokkaido University

Scientists at Hokkaido University have developed a prototype sensor that could help doctors rapidly measures levels of adenosine triphosphate (ATP) and lactate in blood samples from patients, aiding in the rapid assessment of the severity of conditions such as sepsis.

The scientists detailed their prototype biosensor in the journal Biosensors and Bioelectronics.

ATP is a molecule found in every living cell that stores and carries energy. In red blood cells, ATP is produced by a biochemical pathway called the Embden–Meyerhof pathway. Severe illnesses such as multiple organ failure, sepsis and influenza reduce the amounts of ATP produced by red blood cells.

As such, the severity of these illnesses could be gauged by monitoring the amounts of ATP and lactates in a patient’s blood. “In 2013, our co-authors at Tokushima University proposed the ATP-lactate energy risk score (A-LES) for measuring ATP and lactate blood levels to assess acute influenza severity in patients,” explained Akihiko Ishida, an applied chemist at Hokkaido University. “However, current methods to measure these levels and other approaches for measuring disease severity can be cumbersome, lengthy or not sensitive enough. We wanted to develop a rapid, sensitive test to help doctors better triage their patients.”

The researchers developed a biosensor that can detect levels of ATP and lactate in blood with great high sensitivity in as little as five minutes. The process is straightforward. Chemicals are added to a blood sample to extract ATP from red blood cells. Enzymes and substrates are then added to convert ATP and lactate to the same product that can be detected by specially modified electrodes on a sensor chip; the amount of by-product present in the sample increases the electrical current measured.

Schematic representation of the proposed sensor for sequentially detecting ATP and lactate levels in the blood. Through a series of chemical reactions, ATP and lactate are converted to hydrogen peroxide, the breakdown of which to water H2O causes the sensor chip to generate a signal that is detected by the sensor.

The team conducted parallel tests and found that other components present in blood, such as ascorbic acid, pyruvic acid, adenosine diphosphate (ADP), urate and potassium ions, don’t interfere with the ability of the electrodes to accurately detect ATP and lactate. They also compared their sensor with those currently available and found it allowed for the relatively simple and rapid measurement of the two molecules.

“We hope our sensor will enable disease severity monitoring and serve as a tool for diagnosing and treating patients admitted to intensive care units,” said Ishida.

The researchers plan to further simplify the measurement process by integrating an ATP extraction method into the chip itself, as well as reducing the size of the sensor system.

Source: Hokkaido University

Categories : Immune SystemTags :

Degree of Platelet Drop, Not Count, Important in Sepsis Mortality

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Photo by National Cancer Institute on Unsplash

Mortality risk in sepsis is linked to the degree of platelet reduction, rather than absolute platelet count, according to new Japanese research.

Sepsis, a potentially life-threatening condition, arises from tissue and organ damage from an overactive infection response. Sepsis is commonly characterised by abnormally low platelet counts, which is believed to be associated with its high mortality rate.

Recently, Nagoya University researchers and colleagues have shown that a high degree of platelet reduction, rather than an abnormally low platelet count, raises mortality risks in sepsis. The findings, recently presented in the journal Scientific Reports, could lead to the development of precise and preventive treatments for sepsis-associated coagulopathy.

It is known that during sepsis, disseminated intravascular coagulation (DIC) forms tiny blood clots throughout the bloodstream, depleting platelets. Based on this, the international criterion for the diagnosis of sepsis-associated DIC uses platelet count and trials have been done using this criterion. However, very few trials have led to the development of effective treatments for sepsis-associated DIC.

There is however a different theory, that degree of platelet depletion (a rapid drop), rather than the absolute platelet count, accounts for much mortality risk in sepsis-associated DIC. But since there is little evidence for this theory, it has not been considered an international criterion for the disease prognosis.

With this in mind, researchers conducted a study to examine the significance of the degree of platelet reduction on sepsis mortality rate, using data from 200 859 sepsis patients staying in intensive care units of 208 US hospitals.

Corresponding author Dr Daisuke Kasugai of the Nagoya University Hospital, said: “To our knowledge, it was the largest study to evaluate the prognostic impact of both the degree of platelet depletion and absolute platelet counts in patients with sepsis.”

The degree of platelet reductions was found to be associated with the mortality risk associated with sepsis, regardless of absolute platelet count, indicating higher mortality risk with a fast decrease in platelet count. Dr Kasugai said:  “Surprisingly, we also found that if the platelet count decreases by 11% or more, the risks of bleeding, as well as thrombosis development (a serious condition caused by the formation of blood clots in blood vessels or the heart), increases.”

The researchers therefore concluded that, compared to the absolute platelet count, the degree of platelet reduction could be a more plausible criterion for assessing the mortality risk of the sepsis-associated DIC. They hope that this study will lead to effective treatments for sepsis-associated DIC.

Source: Nagoya University

Categories : Medical Research & TechnologyTags :

Artificial Sweetener Delivers a Protective Carbon Monoxide Dose

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Photo by Sharon McCutcheon on Unsplash
Photo by Sharon McCutcheon on Unsplash

An oral prodrug has been developed which uses artificial sweeteners to deliver a protective carbon monoxide dose which protects against acute kidney injury.

Although carbon monoxide (CO) gas is toxic in large doses, with some 50 000 people suffering CO poisoning each year in the US, scientists have discovered it can reduce inflammation and protect cells against injury. The  protective effects of CO against injury in the kidneys, lungs, gastrointestinal tract and liver, among other organs has been shown in previous research. For the past five years, Wang and his collaborators have worked to design a safe way to deliver CO to human patients via prodrugs, which are inactive compounds that must undergo a chemical process in the body to release the active pharmacological agent. Their paper was published in Chemical Science.

Using two common artificial sweeteners, saccharine and acesulfame, as ‘carrier’ molecules for a prodrug, Prof Wang’s team were able to create an oral administration route for CO. They designed the molecules to release CO as they decomposed from water exposure. These are the first examples of orally active, organic CO prodrugs using a benign carrier that is approved by the Food & Drug Administration with a demonstrated safety profile.

“It’s difficult to deliver a gas, much less a poisonous gas, as a therapeutic to patients, and this work represents a pivotal step forward in developing alternative delivery forms,” said Prof Wang, a Georgia Research Alliance Eminent Scholar. “We wanted to work with a carrier that has a very well characterized safety profile, which confers a higher degree of certainty that it will be safe to use in a pill for human consumption.”

The scientists tested one of the prodrugs, CO-306, for pharmacological efficacy against acute kidney damage. CO-306, which uses saccharine as a carrier molecule, was administered to mice and it was found that it reduced biomarkers for kidney injury, indicating it could be developed working therapy. The type of kidney injury modelled mimicked those in humans that occur with extensive muscle damage, sickle cell disease, a common type of malaria, cardiopulmonary bypass surgery and severe sepsis.

Further animal model studies and safety assessments on CO-306 are planned by Wang and colleagues before they progress to human clinical studies. They also plan to test CO-306 for efficacy against other types of organ injuries.

Additionally, CO-based therapies hold promise as a method of reducing the likelihood of organ damage during transplantation and improving outcomes for transplant patients, according to Prof Wang.

“Science shows that exposing organs to CO gas can help preserve organs and prevent them from deteriorating during the process of transplantation,” he said. “Now we need to demonstrate that these prodrugs can have a similar effect.”

Source: Georgia State University

Journal information: De La Cruz, L. K., et al. (2021) Adapting decarbonylation chemistry for the development of prodrugs capable of in vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules. Chemical Science. doi.org/10.1039/D1SC02711E.

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

Sepsis Leaves a Dangerous Imprint in Immune System

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E. Coli bacteria. Image by Gerd Altmann from Pixabay

New research suggests that sepsis can cause alterations in the functioning of defence cells that persist even after the patient is discharged from hospital.

This cellular reprogramming creates a disorder the authors term ‘post-sepsis syndrome’, symptoms of which include frequent reinfections, cardiovascular alterations, cognitive disabilities, declining physical functions, and poor quality of life.This explains why so many patients who survive sepsis die sooner after hospital discharge than patients with other diseases or suffer from post-sepsis syndrome, immunosuppression and chronic inflammation.

The article reviews studies done to investigate cases of septic patients who died up to five years after hospital discharge.

Sepsis is one of the main causes of death in intensive care units, sepsis is a life-threatening systemic organ dysfunction triggered by the body’s dysregulated response to a pathogen, usually a bacterium or fungus. While fighting the pathogen, the defence system injures the body’s own tissues and organs.

If not caught and treated in time, the condition can lead to septic shock and multiple organ failure. Patients with severe COVID and other infectious diseases have an increased risk of developing and dying from sepsis.

Worldwide, new sepsis cases are estimated to reach some 49 million per year. Hospital mortality from septic shock exceeds 40% globally, up to 55% in Brazil, according to the Sepsis Prevalence Assessment Database (SPREAD) study, conducted with support from FAPESP.

“The massive infection and the accompanying intense immune response with a cytokine outpouring during sepsis may promote irreversible cell metabolic reprogramming. Cell reprogramming is unlikely to occur in leukocytes or bone marrow only. This might happen in several tissues and cells that prompt systemic organ dysfunctions […] Bacteria can transfer genetic material to host cell DNA as eukaryotic cells develop tools to protect themselves against the microorganism invasion. The latter may induce cell biology and metabolic reprogramming that remains even after the infection’s elimination,” the investigators wrote in the article.

According to Raquel Bragante Gritte, joint first author with Talita Souza-Siqueira, one of the hypotheses was that metabolic reprogramming begins in the bone marrow, whose cells acquire a pro-inflammatory profile.

“Our analysis of blood samples from patients even three years after ICU discharge showed that monocytes [a type of defense cell] were activated and ready for battle. They should have been neutral. Monocytes are normally activated only when they are ‘recruited’ to the tissue,” Gritte told Agência FAPESP. Both Gritte and Souza-Siqueira are researchers at Cruzeiro do Sul University (UNICSUL) in the state of São Paulo, Brazil.

The researchers conducted a follow-up study of 62 patients for three years after discharge from the ICU at USP’s University Hospital, analysing alterations in monocytes, neutrophils and lymphocytes, as well as microRNAs, in order to identify prognostic markers and factors associated with post-sepsis syndrome.

“Our hypothesis is that white blood cells conserve a memory of sepsis, which helps explain why patients remain sick after they leave hospital,” said co-author Rui Curi, Professor at UNICSUL, and Director of Butantan Institute.

The investigators suggest that sepsis may create a specific macrophage phenotype that stays active even after hospital discharge. “Cell metabolism reprogramming is also involved in the functions and even generation of the different lymphocyte subsets. Several stimuli and conditions change lymphocyte metabolism, including microenvironment nutrient availability,” they wrote.

The next stage of research will be bone marrow studies to understand how cells are reprogrammed by sepsis. “We think the key to this alteration is in bone marrow,” she said. “However, another possibility is that activation occurs in the blood. We’ll need to do more in-depth research to find answers.”

Source: News-Medical.Net

Categories : Diseases, Syndromes and Conditions Hospitals PaediatricsTags :

Children with Sepsis Respond Better to ‘Relaxed’ Care Bundle

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Following a ‘relaxed care bundle’ was linked to lower 30-day mortality and shorter hospital stays among children with sepsis, according to preliminary data from the Improving Pediatric Sepsis Outcomes (IPSO) FACTO trial.

The study findings were presented virtually at the Society of Critical Care Medicine’s Critical Care Congress.

Sepsis is the leading cause of death in children, with an estimated 7.5 million deaths a year. Childhood sepsis includes severe pneumonia, severe diarrhoea, severe malaria, and severe measles. Some 25-40% of children who recover from sepsis still have long-term consequences.

The ‘relaxed’ sepsis bundle is based on a group of best evidence-based interventions. It involves an initial fluid bolus delivery within 60 minutes, as opposed to 20 minutes; and antibiotic delivery within 180 instead of 60 minutes. Accepted sepsis recognition protocols (screen, huddle, or care order) were also involved with the bundle.

This trial data came from about 40 000 patients with sepsis or suspected sepsis at a range of children’s hospitals across the US, from 2017 to 2019. Raina M Paul, MD, of Advocate Children’s Hospital, Illinois, USA reported the data, saying that the relaxed bundle saw better outcomes than the more original bundle which was more time-restrictive. 
Sepsis-attributable mortality fell by 48.9% among the relaxed bolus-compliant versus non-compliant group (3.1% vs 3.5%), and by 13.7% in original bundle-compliant vs non-compliant cases. Following all aspects of the relaxed bundle was associated with a reduction in median days in hospital from 9 to 6 days.

In a separate presentation, Kayla Bronder Phelps, MD, of CS Mott Children’s Hospital in Michigan, USA, reported the results of a study that showed children hospitalised for severe sepsis were likely to have longer hospital stays if they were from lower-income neighbourhoods. Using a national database, she identified 10 130 cases of children with severe sepsis. Severe sepsis hospitalisations were also highest among the lowest-income quartile, reflecting the fact that there were more children living in low-income neighbourhoods.

Overall, 8.4% of children in the cohort died of sepsis during hospitalisation, with no association between mortality rates and income level. However, children in the lowest-income areas spent a median 9 days in the hospital, while children from the highest-income areas spent 8 days.

Bronder Phelps noted that the study is among the first to examine the impact of poverty on paediatric sepsis outcomes. Poverty is a known risk factor for a wide range of paediatric diseases, such as neonatal bacterial infection, asthma, and migraine, and in adults, poverty is associated with poorer outcomes including higher mortality rates.

Source: MedPage Today

Presentation information 1: Paul R, et al “Improving pediatric sepsis outcomes for all children together (IPSO FACTO): Interim results” SCCM 2021; Abstract 32.

Presentation information 2: Phelps K, et al “The association of socioeconomic status and pediatric sepsis outcomes” SCCM 2021; Abstract 37.