Nature Sub-Journal: How Inflammation Caused by Injury or Illness Recovers

• The new findings provide insight into the recovery of inflammation caused by a wide range of injuries or acute diseases

  
  

• The researchers defined common health trajectories based on how quickly white blood cells and platelets returned to normal after the inflammatory response

• This finding could help clinicians recognize and intervene more quickly when the recovery process is not going well

• The team's ultimate goal is to establish a personalized recovery trajectory that enables patients to recover from a wide variety of medical and surgical conditions and can be used in clinical settings

  
  

Inflammation is the body's first line of defense, with swarms of immune cells rushing to the site of injury or acute illness to repair and prevent further damage

Once successful, inflammation helps the body survive and heal

But how do you tell the difference between good inflammation recovery and poor inflammation recovery?

A new study, led by researchers at Harvard Medical School and Massachusetts General Hospital, published Aug.

The scientists identified common features

If confirmed in further studies and eventually become clinical guidelines, these findings could help clinicians identify individual patients' recovery more quickly, allowing them to intervene

An ancient process

Inflammation is a universal response to almost all diseases – hence, people have been trying to describe it

While clinicians today are adept at identifying patients who are experiencing inflammation based on symptoms such as high white blood cell counts or fever, "there is no guidance to assess how inflammation progresses and whether it subsides in an appropriate way," said

However, it is crucial to understand whether inflammation responds effectively to the disease and recovers gradually, as this can help doctors decide whether to stand by and let the patient's body heal on its own or intervene

Higgins and his team began to understand the recovery of inflammation to determine if successful recovery had common features

Signs of success

Because inflammation occurs in patients who are already sick, this can be a complex research process

"We need to find a situation where everyone starts out in the same overall stable state of health, and then they all get a similar inflammatory stimulus at a specific time," explains first author Brody Foy, a systems biology researcher at

They opted for non-emergency cardiovascular surgery — more specifically, coronary artery bypass surgery, valve replacement surgery, or some combination

To determine the pattern of inflammation recovery, the researchers, in collaboration with author Thoralf Sundt, the Edward D.

In patients with good postoperative recovery, the white blood cell count decreases at a precise rate, while the platelet count increases

"Doctors are often unable to track changes in 20 different variables at the
same time.
We really hope to be able to define a good recovery with a small number of measurements that doctors and even patients are already familiar with," said author Jonathan Carlson, a hematologist and researcher at
HMS and MGH.

The team then expanded the study to other types of surgery, including amputation, hip replacement, caesarean section, partial colon removal, and a complex pancreatic surgery, Whipple
.
They also looked at infections that cause inflammation, such as COVID-19 and Clostridium difficile colitis, as well as life-threatening inflammatory response sepsis
triggered by infections.
Finally, they analyzed recovery patterns after events such as heart attacks and strokes, which can lead to tissue hypoxia and trigger abnormal inflammation
.

The researchers found that patients who recovered well followed the same characteristic trajectory, returning to the normal range, just like their counterparts in cardiovascular surgery — and regardless of their condition or age
.
These patterns are consistent
regardless of how quickly patients recover, or what levels their white blood cell and platelet counts begin to reach.

In addition, scientists can mathematically pinpoint the trajectory of recovery success: white blood cell counts undergo exponential decay, while platelet counts increase
linearly after a short delay.

Higgins said: "What's exciting about this study is that it shows that many disease recovery pathways have common characteristics, and if we know what a good recovery is, then we should be able to identify bad recovery
.
"

Translation results

For Higgins, the trajectory of recovery from these inflammations is reminiscent of the so-called Anna Karenina principle popularized by Jared Diamond in his book Guns: there is only one way that things can go well, but many cases go wrong
.
Patients with a good recovery typically follow a predictable pattern of decreasing and increasing WBC and platelet counts, while those with poor recovery may have had too high or too low WBC counts—or not changing
at all at the expected rate.

He also compared it to the Child Growth Chart, where each child's weight and height started at a different point, but should follow the same growth trajectory to stay at a similar percentage
.
He hopes his team will eventually be able to produce similar inflammation recovery charts that personalize health trajectories
for patients with a variety of diseases.

Higgins and his team are working to hand over their findings to clinicians to help them better understand how patients recover from inflammation
.

To illustrate this point, Higgins highlighted the case
of a 78-year-old woman who was admitted to the hospital for a heart attack.
On the fourth day of her recovery, her white blood cell count dropped to the normal range, indicating that she was recovering well
.
However, her white blood cell count remained higher than the health trajectory defined by the researchers — and over the next few days, as the condition worsened, the white blood cell count continued to increase
.
In other words, Higgins said, the overall pattern provides a more valuable diagnostic clue than an absolute blood count because it indicates a problem
with the patient's recovery process by a day earlier.

However, Higgins cautions that it remains to be seen whether early intervention based on these poor harbingers of recovery might improve outcomes
.
That was a subject
that required further study.

Higgins said: "Our method is really just to identify high-risk patients
.
" "We still need to investigate whether a little bit of a diagnosis a little bit earlier would really help, but at least we have a chance to intervene
.
"

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

Higgins said: "These findings help to generate some assumptions about the
mechanism.
" For example, it instructs researchers to observe when the white blood cell count peaks during inflammation and to explore the processes
in the body that lead to exponential decay after peaking.

The researchers also wanted to divert their attention early in the process to see if they could find common features
of how well patients responded well when inflammation first appeared after an injury or illness.

"A quantitative understanding of what a good recovery looks like from the start will allow us to identify at-risk patients at an earlier point in time and design interventions to improve outcomes," said author Aaron Aguirre, an assistant professor of medicine at
Massachusetts General Hospital.

The study was supported
by the One Brave Idea Initiative, the Mocatus Center rapid grant from George Mason University, the National Institutes of Health (DP2DK098087), the Clean Competition Research Partnership, the MGH Hassenfeld Award, and the Risk Control Insurer/Risk Management Foundation.

Article title

Human Acute Inflammatory Recovery is Defined by Co‐Regulatory Dynamics of White Blood Cell and Platelet Populations