A genomic storm

 

Consider two different trauma patients with the same injuries. Both drivers strike a tree with their car. The 20-year old has a moderate concussion, a bruised lung, a few rib fractures, a broken leg and lacerated spleen. He most certainly will bleed into shock at the scene, but is likely to make it to the hospital where his injuries will be treated straightforwardly. In most cases, if the lung and brain contusions improve, the 20-year old will wake up and will probably be discharged from the hospital in 4-7 days. Contrast this patient with a 55-year old with the same traumatic injuries. The 55-year old could easily still be in the intensive care unit long after the younger man has been discharged from the hospital. The older patient also might have many complications from his injuries like sepsis or organ injury. Wouldn’t you think that their genomic responses to the same injuries would be different for many reasons, among them their differences in age, days in the hospital, drugs received, and clinical recovery? Read More

Genomic changes associated with severe blunt trauma

&copy Xiao et al. Originally published in Journal of Experimental Medicine. 208:2581-2590. doi: 10.1084/jem.20111354

Severe injury produces a genomic storm that alters >80% of the leukocyte transcriptome

It turns out that severe injury alters the gene expression of more than 80% of the leukocyte (white blood cell) genome during the first 28 days after injury, which “Inflammation and the Host Response to Injury” Glue Grant investigators call a ‘genomic storm’.  The investigators are not aware of any tumor or other clinical condition associated with such diversity and magnitude of genomic changes. This storm, however, is neither chaotic nor erratic, but rather highly coordinated within an individual and reproducible between individuals. Both in blunt trauma and burn injuries, these dramatic changes occur rapidly within 4 to 12 hours and are prolonged for days or weeks or even months. These findings are the first description of the human genomic response to severe trauma and the different clinical courses a patient can take towards recovery. This work was conducted in over 2,500 critically ill trauma and burn patients and examined the systematic changes in gene expression produced by injury serious enough to be lethal.

Unexpected findings

The findings also show that trauma patients with the complicated (the 55-year old) versus the uncomplicated (the 20-year old) clinical recoveries exhibit remarkable similarities in gene expression patterns with selective differences only in magnitude and duration of the gene expression changes. By this, the investigators mean that there are no genes seen in uncomplicated patient that are not also seen in the complicated patient. Furthermore, all genes that respond to the injury go in exactly the same direction at the same time, either up or down. The magnitude of response might be less in the patient with an uncomplicated case and the time required for those changes to normalize might be shorter. The results did not change significantly when factoring in the number of blood transfusions and injury severity, both of which are increased in patients who have a complicated clinical course after injury. When comparing the two patient groups, uncomplicated with complicated, there were only 63 genes with magnitude and recovery times that were very different.

A new paradigm

&copy Xiao et al. Originally published in Journal of Experimental Medicine. 208:2581-2590. doi: 10.1084/jem.20111354

Changes in both innate and adaptive immunity occur simultaneously, not sequentially, after severe injury

After injury, there occurs a systemic inflammatory response syndrome (SIRS), which is pro-inflammatory and can be associated with serious organ failure and potentially early death. Current beliefs held by critical care specialists say that after a period of 2-4 days, a compensatory anti-inflammatory response syndrome (CARS) is seen. If a “second hit” like a complication develops, the SIRS can be reinvigorated and organ dysfunction and death can result.  In these findings, the early gene changes and continuous genomic recovery over 28 days and beyond in the circulating white blood cells are not consistent with a second-hit phenomenon causing recurrent major systemic inflammatory responses.  Initiation of these processes at the level of the leukocyte transcriptome occurs early and simultaneously with the activation of inflammation and innate immunity.

Perspectives

These are critical points for the development of new predictive tools and therapeutics, which have failed miserably based upon the current dogma.  The Glue Grant findings show that there is a very early (within hours) response in which the innate immune system is activated and the adaptive or acquired immune system is suppressed transcriptionally. The innate immune system is the body’s always present, first line of defense against organisms that could harm while the adaptive immune system includes specialized responses called into action against organisms that overwhelm the body’s innate immune system. Possibly, these changes in the innate and adaptive immune systems may become evident only hours or days later.

Taken together, these findings dramatically change how clinicians view severe injury from a genomic point of view, and challenge the current dogma regarding the underlying mechanisms of multi-system organ failure in critically ill patients. The same genomic changes occurring in both the uncomplicated and complicated patients suggests a common inflammatory stress response, which is unlikely to be distinguishable by a single or small subset of biomarkers. Because it appears that changes in both innate and adaptive immunity are established soon after injury, early, targeted therapy to either or both immune pathways may be the approach that has the best possibility of improving patient outcomes.

Relevant publications

Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Gao H, Inflammation and Host Response to Injury Large-Scale Collaborative Research Program. A genomic storm in critically injured humans. J Exp Med. 2011 Dec 19;208(13):2581-90.  PubMed PMID: 22110166; PubMed Central PMCID: PMC3244029

Contact

Ronald Tompkins, M.D., Sc.D. Wenzhong Xiao, Ph.D. Lyle Moldawer, Ph.D. Ronald Maier, M.D.
rtompkins@mgh.harvard.edu wenzhong.xiao@mgh.harvard.edu moldawer@surgery.ufl.edu ronmaier@u.washington.edu
617-726-3447 617-724-7261 352-265-0494 206-744-3299

 

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