<strong>выключение цитокинового шторма</strong>

Cytokine Storm Syndrome: Symptoms, Diagnosis, and Treatment

<strong>Understanding Cytokine Release Syndrome (CRS) in Cancer Treatment</strong>

Новая модель мышей для изучения цитокинового шторма при нарушении сна

Для данного исследования авторы разработали новую модель мыши для изучения цитокинового шторма, называемую предотвращение кудрения водой. Она основана на том, что мышей не позволяют принимать положение для сна, помещая их в клетку с водой до икры. Через четыре дня у мышей развилось повреждение множественных органов, увеличение продукции противовоспалительных цитокинов и накопление циркулирующих нейтрофилов, вызывающее смерть 80% мышей. Мыши, получавшие ацетаминофен или кортикостероиды, способные подавлять воспалительные цитокины, оказались устойчивы к смертельному воздействию нарушения сна. Также мыши, лишенные рецептора общей γ-субъединицы цитокинов, центрального компонента сигнального пути цитокинов, а также мыши, у которых исчерпаны нейтрофилы, оказались устойчивы к смерти в результате нарушения сна.

Соответствующий автор

Для связи обращайтесь к Александре Флемминг.

Права и разрешения

Флемминг, А. Нарушение сна вызывает цитокиновый шторм. Nat Rev Immunol 24, 2 (2024). https://doi.org/10.1038/s41577-023-00980-9

Графический абстракт. Кредит: Cell Reports and Cincinnati Childrens

Предшествующий пандемии COVID-19, возможно, в основном ученые в лабораториях и врачи на отделениях интенсивной терапии осведомлены о опасной форме запускаемой инфекцией бегущей воспаления, известной как цитокиновый шторм. Однако когда реакции цитокинового шторма, связанные с COVID-19, начали уносить тысячи жизней, ученые мобилизовались, чтобы найти потенциальные терапевтические ответы.

Исследование, проведенное специалистами по иммунобиологии в Cincinnati Children’s и описанное в Cell Reports Эффекторные памятные Т-клетки индуцируют врожденное воспаление, вызывая повреждение ДНК и нестандартный путь STING в дендритных клетках, раскрывает новые важные детали о том, как два элемента иммунной системы организма взаимодействуют друг с другом, чтобы запустить цепную реакцию, которая может вызвать смертельные наводнения клеточного уничтожения и повреждение органов цитокинами.

Эти результаты имеют значение как для автоиммунных заболеваний, так и для рака, — сказал соавтор Чандрашекхар Пасаре, ветеринар и доктор философии, директор отделения иммунобиологии и совместный директор Центра воспаления и толерантности в Cincinnati Children’s. Мы открыли независимый сигнальный путь клеток иммунной системы, называемых эффекторные памятные Т-клетки (TEM), который позволяет им стать важным стимулятором врожденных цитокиновых штормов.

Возникновение COVID-19 инициировало давно нужную классификацию цитокинового шторма для клиницистов

PHILADELPHIA — One of the most elusive aspects for clinicians treating COVID-19 is the body’s immune response to the virus. In the most severe cases of COVID-19, the immune system goes into overdrive, resulting in a fever, multi-organ system damage, and often death — a cytokine storm. But how to detect and treat a cytokine storm requires that clinicians can identify it as such.

Two Penn Medicine researchers have developed a unifying definition of “cytokine storm” to provide physicians with a framework to assess and treat severely-ill patients whose immune systems have gone rogue. Cytokine storms can be triggered by different pathogens, disorders, or treatments, from COVID-19 to Castleman disease to CAR T cell therapy.

“There has never been a defining central review of what a cytokine storm is and how to treat one, and now with COVID-19, that is a major issue,” said Fajgenbaum, a Castleman disease patient who has previously experienced five cytokine storms himself. “I’ve spent the last 10 years of my life as a cytokine storm patient and researcher, so I know the importance of having a comprehensive unified definition to find therapies that work across the various types of cytokine storms.” Fajgenbaum’s CSTL has discovered novel therapeutic approaches for the cytokine storm with Castleman disease, including a treatment that Fajgenbaum is taking himself and studying in a clinical trial.

There is widespread recognition that the immune response to a pathogen, but not the pathogen itself, can contribute to multi-organ dysfunction and other symptoms. Additionally, similar cytokine storm syndromes can occur with no obvious infection.

A host of other disorders have also been described as causes of cytokine storms and targeted with immune-directed therapies, such as sepsis, primary and secondary hemophagocytic lymphohistiocytosis (HLH), autoinflammatory disorders, and now SARS-CoV-2.

Fajgenbaum and June report that it is typically easy to identify a cytokine storm in disorders with elevated cytokines where there are no pathogens. However, the line between a normal and a dysregulated response to a severe infection — like COVID-19 — is blurry, considering that certain cytokines may be both helpful in controlling an infection and harmful to the individual. The interdependence of these inflammatory mediators makes it even more complex.

“When COVID-19 hit, it reminded us how critical it is to define the difference between this hyper immune response and an appropriate inflammatory response,” June said. “Our goal here is to chart a clearer path forward by putting clinical teams in a better position to recognize and appropriately manage a cytokine storm caused by the coronavirus and other triggers.”

Fajgenbaum and June maintain that the approach to evaluating a patient with a cytokine storm should accomplish three main goals: identifying the disorder underlying the cytokine storm and ruling out conditions that may mimic a cytokine storm, establishing severity, and determining the optimal therapeutic approach for the patient.

Targeted therapeutic approaches for cytokine storm in Castleman disease, HLH, and CAR T cell cancer immunotherapy have turned these deadly conditions into often reversible states. The CSTL has been searching for and systematically tracking treatment approaches for COVID-19 to identify similarly promising treatments. Given advances in integrated analysis across systems — like the genome, microbiome, epigenome, transcritptome, etc. — called multi-omics, and therapeutic modulation of the immune system, as well as concerted efforts to work across the cytokine storm umbrella, Fajgenbaum and June expect to see continued improvements in outcomes.

“We wanted to create a definition that was really exhaustive of the various cytokine storms that can occur — what causes them, what are some of the underlying mechanisms, and maybe most importantly, what are our current therapy options and what needs to be done in the future to make treatment of cytokine storms more effective,” Fajgenbaum said.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Home Care and Hospice Services, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2018, Penn Medicine provided more than $525 million to benefit our community.

If you’d like to read the full text, please access the New England Journal of Medicine’s website here.

What is a cytokine storm?

Cytokines are protein molecules that play an important role in stimulating immune system cells. The body makes them when exposed to infections as part of its inflammatory response. The molecules control the growth and activation of immune system cells and blood cells, acting as chemical messengers that tell the immune cells what to do and prompt the body to produce even more immune system cells.

Immunotherapy drugs also trigger cytokine releases. Scientists are still trying to understand why a release may become a cytokine storm in some patients and why they trigger such a hyperproduction of cytokines that a patient may experience organ failure or other serious side effects.

“No single definition of cytokine storm or the cytokine release syndrome is widely accepted, and there is disagreement about how these disorders differ from an appropriate inflammatory response,” said David C. Fajgenbaum, MD, and Carl H. June, MD, of the University of Pennsylvania in a December 2020 review article in the New England Journal of Medicine. “The line between a normal and a dysregulated response to a severe infection is blurry, especially considering that certain cytokines may be both helpful in controlling an infection and harmful to the host.”

“This is not something that smolders for weeks and weeks,” Jeremy T. Larsen, MD, Hematologic Oncologist at City of Hope Cancer Center Phoenix, said in a Sept. 18 article in the journal Oncology. “These are a median duration of a couple of days and are reversible. This is not a manifestation that’s resulting in patients discontinuing therapy.”

CRS causes a variety of symptoms that doctors need to be on the lookout for, including:

“Patients react with the same kind of symptoms that they would if they had an infection,” Dr. Popplewell says. “That can include minor things like body aches, and in general not feeling well, to high fevers. Fevers themselves are not necessarily dangerous, but having a high fever for number of days can lead to other problems.”

Respiratory symptoms are common in CRS and can range from a mild cough to acute respiratory distress syndrome. Potentially life-threatening complications may include cardiac dysfunction, neurologic toxicity and organ failure. In particular, a cytokine storm may damage to the lungs and kidneys.

“I’ve certainly seen patients who simply had severe cytokine release,” Dr. Popplewell says. “Detailed discussion of risks and benefits of this treatment are important.”

Before starting it is important to talk about the likelihood of reactions and what will be done to monitor the patient and what interventions are available.

Causes of Cytokine Storm Syndrome

Scientists are still working to understand the complex web of causes that can cause cytokine storm to start. Several different types of underlying health issues may cause it.

People with certain genetic syndromes are more likely to experience cytokine storm. For example, this applies to people with a condition called familial hemophagocytic lymphohistiocytosis (HLH). These genetic defects lead to specific problems in certain immune system cells.

People who have a genetic condition in this group are more likely to develop cytokine storm in response to infections. This usually happens within the first few months of life.

Certain types of infections can also trigger cytokine storm in some people, including those caused by:

One of the most commonly studied types is cytokine storm from influenza A virus. This is the virus that causes the common flu. Severe types of influenza infections may be more likely to cause cytokine storm.

For example, it’s thought that cytokine storm syndrome might have been the reason for the high death rate in young adults during the 1918 influenza pandemic. Epstein-Barr virus and cytomegalovirus are some other common infectious causes.

Even though most people don’t experience cytokine storm, certain types of infections are more likely to cause it than others.

For reasons that aren’t yet completely clear, the SARS-CoV-2 virus that causes COVID-19 seems more likely to result in cytokine storm compared to diseases caused by some other viruses. That’s a big reason why the virus poses such a worldwide problem.

People with certain autoimmune syndromes have a higher risk of getting cytokine storm syndrome. For example, this can occur in:

In this context, cytokine storm often goes by the name “macrophage activation syndrome.”

This type of cytokine storm might occur when a person’s underlying disease is flaring up. And it can also happen when the person is also experiencing some kind of infection.

Cytokine storm can also sometimes be a side effect of specific medical therapies. For example, it has sometimes occurred after a therapy for leukemia known as CAR-T therapy, also known as chimeric antigen receptor T cells. Other types of immunotherapy have also sometimes caused cytokine storm as a side effect.

Cytokine storm can also occur in other medical situations, such as after receiving an organ or stem cell transplant. Certain types of cancers may also cause a cytokine storm syndrome. Conditions that affect the immune system, like AIDS, can also cause it.

Sepsis, a life-threatening immune response to an infection, is also sometimes broadly thought of as being a type of cytokine storm syndrome.

Cytokine storm treatment

Still, as the teclistamab study showed, CRS is often treatable and manageable if doctors pay attention to the clues and watch for early signs of CRS disease as soon as treatment starts. That’s why CAR T-cell therapy, for instance, is typically delivered in a hospital setting and not on an outpatient basis.

Treatment options include immunosuppressive drugs such as steroids, or monoclonal antibodies like tocilizumab (Actemra®).

In the teclistamab study, tocilizumab reduced the risk of a subsequent CRS episode in patients receiving it. The study said 20 percent of those receiving tocilizumab didn’t have another CRS event, compared to 62.2 percent of those who didn’t receive the drug.

In the Oncology article, Dr. Larsen said he might observe patients who have light fevers for a few hours without giving tocilizumab, but he’d use the drug for patients with “bona fide fevers.” If the fever lasts, he may turn to steroids, which he also uses to manage cases of neurotoxicity, the second leading side effect in CAR T-cell patients.

“Neurotoxicity is something we don’t really understand as well as we do cytokine release syndrome,” Dr. Popplewell says. “Patients can develop confusion and, in some cases, seizures after CAR T-cells are given. And that’s why it’s critical to partner with neurologists who can help with diagnostic procedures and provide support. We give anti-seizure medication as a precaution.

One area of treatment where more study is needed is the pre-emptive use of tocilizumab or steroids prior to CAR T-cell treatment or prior to CRS symptoms appearing.

A 2021 study in the Journal of Clinical Oncology showed that risk-adapted use of tocilizumab before CAR T-cell therapy in the treatment of CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia “resulted in a decrease in the expected incidence of grade 4 CRS.”

Dr. Popplewell says some centers may use tocilizumab or steroids prior to cytokine storm symptoms have a chance to develop in patients who are elderly or who doctors think will not tolerate a CRS reaction well.

Dr. Larsen would like to see more data before considering the prophylactic use of these immunosuppressants as a standard practice for CAR T-cell therapy. However, if such treatment is shown to reduce the frequency and severity of CRS, he said it may lead to shorter hospital stays and improved outcomes.

Cytokine Storm and COVID-19

In people experiencing cytokine storm syndrome, certain cytokines are present in the blood at higher-than-normal amounts. In COVID-19, elevations in several inflammatory cytokines seem to be involved in the development of acute respiratory distress syndrome, the leading cause of death in people dealing with COVID-19 illness.

People hospitalized in the ICU from COVID-19 seem to have more elevations in certain inflammatory cytokines compared to other individuals who are infected but less ill.

Most people with COVID-19 do not develop cytokine storm and its symptoms. Certain people may be more prone to developing cytokine storm from COVID-19 if they have specific genes that make their immune system react in certain ways.

At this point, this is not known for sure. Other factors, such as the presence of underlying health conditions, may determine how severe your COVID-19 infection will be.

Cracking the activation mechanism

Bowler and a former PhD student in his lab, Erika Pellegrini, have therefore been investigating the interactions between p38α and MKK6 – the kinase which activates it – since 2009. But studying the interaction between kinases proves to be extremely complex. “These enzymes are very dynamic molecules; they transmit important signals and need to act quickly. In the case of p38α, it has to go into the nucleus and activate lots of other different proteins,” said Bowler.

They were hampered by the fact that the interactions of the MKK6-p38α complex cannot be determined by macromolecular crystallography, a structural biology technique often employed to investigate proteins but that is particularly challenging to apply in the case of such dynamic proteins.

Recent developments in cryo-electron microscopy (cryo-EM), particularly during the last decade, raised new hopes. In 2016, Bowler and new PhD student and first author of the paper, Pauline Juyoux, decided to switch to this technique – even though the protein complex was at the time considered too small for cryo-EM analysis. They were supported by Pellegrini, who had acquired expertise in this technique.

Tenacity and collaboration were key contributors to project success. “There were a lot of ups and downs, but there were always inspiring people or moments – one of these being particularly memorable,” remembered Juyoux. “We obtained the first low-resolution 3D negative stain model on the exact same day that the Nobel Prize was announced for cryo-EM in 2017. It gave us a boost of motivation!”

A collaboration with the Gervasio Lab from the University of Geneva, which uses molecular dynamics simulations, supported Bowler, Pellegrini, and Juyoux in giving further insight into how the two kinases interact. “They showed that the model we had generated was compatible with the enzymatic activity and that the phosphorylation site was at the right distance from the active site,” explained Juyoux. “They also classified the different types of conformations of the complex to show how they assemble.”

Crucially, by comparing these simulations with the SAXS data they were able to model how the two proteins interact prior to catalysis. “The beauty of combining the state-of-the-art simulations with SAXS and cryo-EM data through advanced statistical approaches is that we can ‘see’ the dance of the two kinases approaching one another, while knowing that what we see in the computer is fully supported by all the experimental data available,” explained Francesco Gervasio. “The simulations required several months of supercomputing time generously allocated by the Swiss National Supercomputing Centre,” he continued, “But it was well worth it, given the relevance of the final results.”

Graphical abstract illustrating MAP kinases p38α and MKK interactions and conformation states. Credit: Pauline Juyoux/EMBL

These results provide an alternative drug target site to explore and also open the door to studying similar processes in two other families of MAP kinases: ERK kinases – which are involved in cancer – and JNK kinases – also involved in inflammation, especially in Alzheimer’s disease.

“Kinases are very similar to one another in terms of sequence and structure, but we don’t know how and why they respond or send a specific signal,” said Juyoux, whose current research project as a postdoctoral fellow at Institut de Biologie Structurale in Grenoble focuses on JNK kinases. “Comparing these different families of kinases could help explain the specificity of interactions and lead the way to new therapeutic approaches.”

Source article(s)

Juyoux P., et al.

Science 14 September 2023

Cytokine Storm Symptoms

Cytokine storm symptoms are varied and might include:

Very low blood pressure and increased blood clotting can also be signs of severe cytokine storm syndrome. The heart may not pump as well as it normally would. As a result, cytokine storm can affect multiple organ systems.

A Word From Verywell

Cytokine storm syndrome is a problem of immune system dysregulation that may cause life-threatening symptoms. It’s scary and frustrating to learn that someone you care about is battling such a problem. However, know that you aren’t alone. Medical professionals will do everything possible to make sure your loved one receives the best possible care.

Frequently Asked Questions

Cytokine storm is a cascade of exaggerated immune responses that can cause serious problems. It is not considered a disease in itself, but rather a serious medical issue that can happen because of several underlying issues. It is also sometimes called cytokine release syndrome, CRS, or just cytokine storm.

The immune system has many different components that help you battle infections. It includes many different types of cells that communicate with each other using signaling molecules. These molecules are known as cytokines.

Many different cytokines perform many kinds of functions. Some help recruit other immune cells, and some help with antibody production or pain signaling. Some make the blood clot more easily. Some help produce inflammation. This can make blood vessels more leaky than normal.

Another group of cytokines helps tamp down the body’s inflammatory response. That’s an important balance. This is because too much inflammation causes its own problems.

Under normal circumstances, these cytokines help coordinate the response of your immune system to take care of infectious substances, like viruses or bacteria. The problem is that sometimes the body’s inflammatory response can get out of control. This causes more harm than good.

Sometimes the body produces too many inflammatory cytokines and not enough cytokines that control inflammation. The inflammatory cytokines start “storming” out of control, without enough feedback from the anti-inflammatory cytokines.

Cytokine Storm Syndrome Diagnosis

Doctors consider the underlying medical condition when diagnosing cytokine storm. This underlying problem might be already known, or it may require its own diagnosis.

A person might need to be diagnosed with:

Depending on the situation, this might require various kinds of medical tests, like specific blood tests.

Medical history and a physical exam provide diagnostic starting points. Your clinician will want to know about your past medical issues and recent symptoms.

The clinician will also thoroughly examine you for signs that might indicate cytokine storm. This is important because cytokine storm can affect so many different systems of the body. The clinician may disover that you have:

It’s important for clinicians to recognize that cytokine storm is a possibility because it is such a dangerous condition.

Medical imaging can also provide clues. For example, a chest X-ray might display lung involvement from cytokine storm related to COVID-19.

It is important to realize that the term “cytokine storm” might not come up at all, even if that is part of the problem. It isn’t always diagnosed or mentioned specifically.

You might just learn that someone is having severe symptoms from influenza, COVID-19, or another condition. Tests to verify that cytokines are elevated might not be helpful or necessary.

Researchers are working hard to understand what cytokine storm means in the context of COVID-19. Some clinicians have suggested screening patients with the disease for laboratory signs of inflammation that might indicate a cytokine storm, like elevated ferritin levels.

It has been suggested that these individuals might benefit from therapies targeted to address cytokine storm and tamp down the immune system. However, this is not yet clear.

In some situations, it may be possible to treat the underlying source of the cytokine storm. For example, if cytokine storm is caused by a bacterial infection, an antibiotic may be helpful.

However, in many cases a direct treatment for the underlying condition is not available, and clinicians must try other approaches to try to decrease the immune response. But it is very complicated, in part because the immune system has so many different parts.

In fighting off an infection, it might be ideal to tone down one part of the immune response while leaving another part working normally, or even strengthening it.

Many different therapies have been tried, but scientists do not currently agree about the best way to treat cytokine storm in all circumstances. The best options may depend somewhat on the specific underlying cause of the cytokine storm.

For example, corticosteroids seem to be very helpful for people with cytokine storm due to underlying autoimmune disease. However, it’s not clear that this is the best option for people with cytokine storm from an infectious cause, like in COVID-19.

Timing may also be critical for effective therapy, since treatments that might be helpful early might not be effective later, and vice versa. There may also be a lot of variability in how people respond to such therapies.

In the past, some treatments have been tried for cytokine storm with some mixed success. These include:

Treatment of Cytokine Storm from COVID-19

Researchers are actively exploring many different therapies to treat cytokine storm syndrome from COVID-19. Many are studying existing therapies that affect the immune system to see if any might help people with cytokine storm from COVID-19.

Researchers are currently studying whether this therapy might help critically ill people with cytokine storm syndrome from COVID-19.

Scientists are currently investigating these therapies, as well as many other potential interventions. Ideally, multiple therapies will be found to help curb the effects of cytokine storm, leading to decreased deaths from COVID-19.

The final switch

Bowler’s work particularly focuses on MAP kinases, key players involved in the inflammatory response. Inflammation is switched on via a series of kinases, which activate each other in a cascade of reactions, the final kinase in the series being responsible for activating gene transcription required for inflammation. This process releases cytokines, pro-inflammatory signalling molecules, which, in case of overactivation, can lead to cytokine storms.

This kinase chain reaction is well regulated and is similar to a logic circuit: the inflammation response requires specific buttons to be switched on, ultimately activating p38α – the meeting point where all the signals converge and the last switch of the inflammatory process.

Because the kinase chain reaction can come from different ‘branches’ of the logic circuit, this last switch is a particularly relevant drug target. The inflammatory response is regulated by p38α and is highly activated during a cytokine storm. Inactivating it could prevent inflammation from occurring, instead of trying to treat it while it is already underway.

However, important parts of the puzzles are still missing. “Structural biologists have obtained detailed information on the structure and functions of protein kinases, but mostly in isolation. So we don’t really know how these enzymes are activated along the chain reaction,” explained Bowler.

Without this essential information about how the activation is triggered, drugs have mostly targeted the kinases’ nucleotide-binding site – a common and well-known pocket present in all kinases, where the phosphate transfer occurs. The lack of drug specificity due to a common binding site across kinases means that a drug designed to stop one kinase from signalling could also stop others. This presents a problematic side effect, considering the essential role of kinases as key regulators in cellular processes.

“There are many molecules that have been designed to target p38α, especially its nucleotide-binding site, but none have yet made it past clinical trials due to this lack of specificity,” added Bowler.

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