How recovery progresses following inflammation triggered by injury or disease

Inflammation is the body’s first line of defense, occurring when masses of immune cells rush to the site of acute injury or illness to effect repairs and stem further damage.

If successful, inflammation helps the body survive and heal after trauma. However, when recovery from an inflammatory response goes awry, it signals that damage is still occurring – and the inflammation itself can cause further injury, leading to more serious illness or even death.

But what differentiates a good inflammatory recovery from a bad one?

A new study, conducted by Harvard researchers Medical College and Massachusetts Common Clinic, published August 20 in Mother Nature Communications, provides critical clues.

Scientists have identified universal characteristics of the inflammatory responses of people who have successfully recovered from surgery or acute illnesses such as COVID-19, heart attack and sepsis. These characteristics, they discovered, include specific pathways that white blood cell and platelet counts follow when they return to normal.

If reaffirmed in d further studies and possibly codified as clinical guidelines, the findings could help clinicians more quickly recognize when an individual patient’s recovery is not going well, allowing them to intervene sooner.

An ancient process

Inflammation is a generic response to almost every disease – and as such people have been trying to describe it for thousands of years. In ancient Rome, medical writer Aulus Celsus described the four main symptoms of inflammation: redness, warmth, swelling and pain – and later physician and surgeon Galen added loss of function to the list. Today, scientists know that the symptoms of inflammation occur when the immune system responds to injury or acute illness, sending protective white blood cells, proteins and chemical factors that cause physiological changes in the body. .

Although today’s clinicians are good at identify patients who have inflammation based on signs such as an elevated white blood cell count or fever, “there is no indicator on assessing how the inflammation is progressing and whether it is ‘attenuates appropriately,’ said lead author John. Higgins, professor of systems biology at the Blavatnik Institute at HMS. “As physicians, we are surprisingly ill-equipped to distinguish patients whose inflammatory response is fine from clients whose response is not.”

Yet knowing if Inflammation responding effectively to disease and moving toward recovery is essential, as this can help doctors decide whether to step back and let an individual’s body heal on its own or intervene.

Higgins and his team set out to understand inflammatory recovery to determine if there are common characteristics of successful recovery.

Signs of success

Because inflammation occurs in people who are already sick, it can be a complicated process to study. So the researchers knew that to isolate common features, they would have to study inflammatory recovery in a highly controlled setting.

“We had to find a problem where everyone starts in the same generally secure state of health, then they all receive a similar inflammatory stimulus at a specific minute,” explained first author Brody Foy, HMS systems biology researcher and mass general.

They opted for elective cardiovascular surgery – specifically, coronary bypass surgery, valve replacement or a combination. These procedures are often performed on relatively healthy clients who have underlying heart problems, but who are otherwise stable and not experiencing problems that require immediate treatment. However, all cardiovascular surgery involves considerable trauma and tissue damage when surgeons access the heart for surgical repairs, causing a significant inflammatory response.

To identify patterns of inflammatory recovery , researchers worked with author Thoralf Sundt, HMS Edward D. Churchill Professor of Surgery at Mass Basic, to review data from the medical records of 4 693 Mass Standard patients who have had cardiovascular surgery. After analyzing dozens of measurements simultaneously, they found common features in the trajectories of patients who recovered well. They focused on two variables that reliably identified trajectories of successful inflammatory recovery: white blood cell count, which unsurprisingly increases during inflammation, and platelet count, which decreases as platelets are used for clotting and healing.

Among patients who recovered well after surgery, white blood cell counts decreased at a precise rate, while the platelet count increased at a different, but equally precise rate. These trajectories, the researchers say, can be used to monitor recovery in a personalized way.

“Doctors generally cannot track changes in 20 different variables at a time. We really wanted to be able to define good recoveries in terms of a small number of measures that doctors and even patients already know,” said author Jonathan Carlson, hematologist and researcher at HMS and MGH.

The team then expanded the study to look at other kinds of surgeries that cause significant swelling, including limb amputations, hip replacements, C-sections, partial colon removals and a complex pancreatic surgery called the Whipple procedure. They also looked at inflammatory infections such as COVID-19 and Clostridium difficile colitis, as well as sepsis, an inflammatory response life-threatening precipitated by an infection. Finally, they analyzed recovery patterns after events such as heart attacks and strokes that result in tissue oxygen starvation and can cause aberrant irritation.

Researchers found that people who recovered well followed the same characteristic trajectories for white blood cell count and platelet count returning to normal as their cardiovascular surgery counterparts – regardless of their condition or age. These patterns were also consistent regardless of how quickly the clients recovered or at what level their white blood cell and platelet counts started.

Additionally, the Scientists were able to mathematically define the precise trajectories that indicated successful recovery: white blood cell counts decayed exponentially, while platelet counts increased linearly after a short delay.

“What is exciting about this study is that it suggests that there are common features of the healing pathway for a surprisingly wide range of diseases, and if we know what a good cure, then we should be able to identify a bad one,” Higgins says.

Translate the results

For Higgins, these incendiary recovery trajectories evoke the so-called principle of Anna Karenina popularized by Jared Diamond in his book Guns, Germs, and Metal: There is only one way things can go right, but many ways things can go wrong. Patients who recover well generally follow a predictable pattern of decreasing and increasing white blood cell and platelet counts, while patients who do not recover well may have numbers that are too high or too low – or just don’t. not change at expected rates.

It also compares to pediatric growth charts, in which each child starts at a different place but must follow the same growth trajectory – and therefore stay in a similar percentile – for weight and height. He hopes his team will eventually be able to create analog graphs for inflammatory recovery to personalize healthy trajectories for individual clients with a wide range of diseases.

Higgins and his team are working to put their findings into the hands of clinicians to help them better understand how patients recover from irritation.

To illustrate this idea, Higgins put highlights the case of a 78 year old woman admitted to hospital after a heart attack. On the fourth day of her recovery, her white blood cell count fell within the normal range, suggesting that she was recovering well. However, her white blood cell count was still above the healthy trajectory set by the researchers – and it continued to rise over the following days as she got worse. In other words, the world-wide model provided a more valuable diagnostic clue than the absolute blood count, Higgins said, reporting a day earlier that something had gone wrong with the client’s recovery. .

Higgins, however, cautions that it remains to be seen whether early intervention based on these warning signs of poor recovery could improve outcomes. This is a subject for further research.

“Our approach really just identifies high-risk patients,” Higgins said. “We still need to investigate whether diagnosing something a bit earlier will actually help, but at least we’d have a chance to intervene.”

Higgins and his team are also interested studying the underlying biological mechanisms that cause white blood cell and platelet counts to return or not return to normal after injury or disease.

“These results help generate hypotheses about mechanisms,” Higgins said. For example, it guides researchers to examine when white blood cell count peaks during inflammation and explore processes in the body that would lead to exponential decay after the peak.

The researchers also want to move their record even earlier in the process to see if they can find common characteristics of a good response when clients initially develop irritation after injury or illness.

“Understanding quantitatively what good recovery looks like early on will allow us to identify at-risk patients at even earlier times and design interventions that improve outcomes. results,” said author Aaron Aguirre, HMS Assistant Professor of Medicine at Mass Standard.

The research was supported p ar the One Courageous Notion Initiative, Rapid Grants at the Mercatus Center, George Mason University, the NIH (DP2DK20), the Partnership for Clean up Competitors Investigate Collaborative, the MGH Hassenfeld prize and the Managed Hazard Insurance plan Business/Threat Management Foundation.

Related Articles

Back to top button