Early leukocyte gene expression associated with age, burn size, and inhalation injury in severely burned adults

Abstract

Background In the burn-injured patient, older age, larger percent total body surface area (%TBSA) burned, and inhalation injury are established risk factors for death, which typically results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated these three risk factors. Methods We performed a retrospective analysis of the Glue Grant database. From 2003–2010, 324 adults with ≥20% TBSA burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within one week post-burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold-change threshold of 1.5 and false-discovery rate of 0.05. Results After adjusting for potential confounders, age >60 (RR 4.53; 95% CI: 2.93–6.99), burn size >40% TBSA (RR 4.24; 95% CI: 2.61–6.91), and inhalation injury (RR 2.08; 95% CI: 1.35–3.21) were independently associated with mortality. No genes were differentially expressed in association with age >60 or inhalation injury. Fifty-one probe sets representing thirty-nine unique genes were differentially expressed in leukocytes from patients with burn size >40% TBSA; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of pro-inflammatory cytokines. Conclusions Among adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the “genomic storm” induced by a ≥20% TBSA burn. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns >40% TBSA. Level of Evidence Epidemiologic study, level III.

Genome-wide comparisons of gene expression in adult versus elderly burn patients

“…In contrast, Sood et al analyzed transcriptomic changes associated with burn age, size, and the presence of inhalation injury and established that there were no differentially expressed genes for burn patients aged >60. They do, however, comment that their study was possibly underpowered as only 12% of patients in their analysis were older than 60 and that further studies are needed in this group[24]. Another transcriptomic analysis demonstrated that burn patients hypersusceptible to infection demonstrated suppression of immune cell activation and early alterations in immune-related signaling pathways[25], similar to our findings in elderly patients.…”

“…Although not statistically significant, there is a higher rate of inhalation injury in the elderly group, 40%, compared to 25% in adults. Previous studies have examined transcriptomic expression profiles and inflammatory profiles in patients with and without inhalation injury and found only minor differences[24]. It may still, however, influence results.…”

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“…Neutrophils are immediately activated and migrate to the injury site to remove debris and pathogens as well as promote wound healing after burn injury. 26 , 27 However, they also accumulate in other remote organs, such as the lung and small intestine and eventually lead to the injury of these organs. 28 Overactivated neutrophils can secrete free radicals and inflammatory mediators such as interleukin (IL)-1, tumor necrosis factor (TNF), IL-6, and IL-8 after severe burn injury and result in systemic inflammatory response syndrome and multiple organ failure.…”

Does Acute Kidney Injury Condition Affect Revised BAUX Score in Predicting Mortality in Major Burn Patients?

“…The severity of the body's systemic response to a burn injury is related to the inflammatory cytokine level, which varies with how large the injured area is. 20 Second-degree burns play a significant role in the development of AKI complications. This may be explained by the level of cytokines that are stimulated and secreted.…”