Negative Effects of Trauma May Persist for Decades After the Incident

Exposure to moderate or severe trauma significantly increased the risk of premature death, immune-mediated disease, or cancer as compared with a twin sibling not exposed to trauma, a large matched-pair study showed.

During follow-up for as long as 20 years after the traumatic incident, twins exposed to trauma had a 33% greater risk of death or developing an immune-mediated disease or cancer. Separate analyses of the primary components of the composite endpoint also yielded statistically significant HRs for the trauma-exposed versus unexposed twins.

The results suggest that exposure to severe trauma significantly increases risk of death or serious illness not only close to the trauma but for years afterward, reported Trine O. Eskesen, MD, PhD, of Rigshospitalet Copenhagen in Denmark, and co-authors, in JAMA Surgery.

“Long-term mortality is increased for trauma patients compared with the general population, and our study adds to this body of evidence,” the authors wrote of their findings. “Still, our study differs from other studies by including a twin population and thereby having the best-matched control for the trauma population with long follow-up period.”

“Sensitivity analyses of male, female, monozygotic, and dizygotic twins, respectively, provided similar results,” they added.

The “striking” results not only are informative but suggest questions to explore in future studies, wrote Timothy A. Pritts, MD, PhD, of the University of Cincinnati, in an accompanying editorial.

“The findings of a lack of association of monozygotic compared with dizygotic twinning suggests that there are likely many factors in addition to purely genetic ones that are important to long-term outcomes,” Pritts stated. “In addition, the investigators found that increased Injury Severity Score [ISS] was associated with decreased hazard ratios for reaching the composite outcome. This is highly counterintuitive and should be the subject of further investigation.”

“Furthermore, the median follow-up period of 8.6 years allows substantial room for future study of this population to determine the lifetime effect of trauma on outcomes. Taken together, there is much to be learned — now and in the future — from tales of trauma in twins.”

Studies have shown that mental and physical trauma may increase the risk of other diseases later in life, including evidence of an association between specific organ injury and subsequent cancer diagnosis, the authors noted in the introduction to their findings. Another study showed a significant association between physical/mental stress in childhood and certain autoimmune diseases in adulthood.

Although more research is needed, identifying an appropriate nontraumatized control group is challenging, the authors continued. A population of same-sex twins offers several advantages, such as same age, sex, genetic factors, and household environment.

Eskesen and colleagues hypothesized that exposure to moderate/severe trauma would be associated with an increased risk of death, immune-mediated disease, or cancer, beginning 6 months after the trauma. Using data from the Danish Twin Registry and the Danish National Patient Registry, investigators identified 3,776 twin pairs with discordant trauma exposure, born from 1895 to 2000 and alive and still living in Denmark as of 1994. The median age at the beginning of follow-up was 36.4, and 61% of the twin pairs were male, while 33% were monozygotic twin pairs. The median ISS was 16.

The primary outcome was the composite of death or one of 24 predefined immune-mediated diseases or cancer. Data analysis included 2,290 twins. The remaining twins were excluded because one or both twins had a prior diagnosis of one or more of the outcomes.

Investigators identified the primary composite outcome in 1,268 twin pairs. The twin exposed to trauma reached was the first to reach the primary outcome in 724 twin pairs (32%) compared with 544 (24%) twin pairs wherein the co-twin reached the outcome first. The difference translated into an HR for the composite outcome of 1.33 for the trauma-exposed twins versus the co-twins (95% CI 1.19-1.49).

An analysis limited to death as the outcome yielded a HR of 1.91 for the trauma-exposed twins (95% CI 1.68-2.18). When immune-mediated disease or cancer was the outcome, the trauma-exposed twins had a HR of 1.28 versus the co-twins (95% CI 1.14-1.44).

The finding of an increased mortality hazard in association with trauma added to an existing body of evidence, but the twin pairs provided the best matched control population for a comparison of discordant trauma exposure. The authors speculated that the increased risk of immune-mediated diseases or cancer might have originated from rapid activation of the immune system by trauma.

“At the genomic level, the response to trauma has been referred to as a genomic storm as most of the genome of circulating leukocytes is affected with activations of the innate and suppression of the adaptive immune system,” they wrote. “This may leave an immunological imprint that could be part of a potential causal link between trauma and development of immune-mediated disease later in life.”