Pediatric Burn Survivors Have Long-Term Immune Dysfunction With Diminished Vaccine Response

Abstract

Epidemiological studies have demonstrated that survivors of acute burn trauma are at long-term increased risk of developing a range of morbidities. The mechanisms underlying this increased risk remain unknown. This study aimed to determine whether burn injury leads to sustained immune dysfunction that may underpin long-term morbidity. Plasma and peripheral blood mononuclear cells were collected from 36 pediatric burn survivors >3 years after a non-severe burn injury (<10% total body surface area) and from age/sex-matched non-injured controls. Circulating cytokine and vaccine antibody levels were assessed using multiplex immunoassays and cell profiles compared using a panel of 40 metal-conjugated antibodies and mass cytometry. TNF-α (1.31-fold change from controls), IL-2 (1.18-fold), IL-7 (1.63-fold), and IFN-γ (1.18-fold) were all significantly elevated in the burn cohort. Additionally, burn survivors demonstrated diminished antibody responses to the diphtheria, tetanus, and pertussis vaccine antigens. Comparisons between groups using unsupervised clustering identified differences in proportions of clusters within T-cells, B-cells and myeloid cells. Manual gating confirmed increased memory T-regulatory and central memory CD4+ T-cells, with altered expression of T-cell, B-cell, and dendritic cell markers. Conclusions: This study demonstrates a lasting change to the immune profile of pediatric burn survivors, and highlights the need for further research into post-burn immune suppression and regulation.

Distinct Injury Responsive Regulatory T Cells Identified by Multi-Dimensional Phenotyping

“…Consistent with this, it has been demonstrated that pediatric burn patients have increased levels of circulating memory Tregs that resemble these injury responsive CD44 high Tregs in mice. These burn victims also showed long-term lower vaccine responses than uninjured controls, supporting our findings that injury-responsive memory Tregs are highly immunosuppressive ( 47 ). Consistent with our findings in mice, trauma patients have increased circulating levels of Tregs that can more potently suppressive T cell proliferation and patients that develop infections or sepsis showed higher circulating levels of Tregs ( 9 , 48 ).…”

Systemic long-term metabolic effects of acute non-severe paediatric burn injury

“…The expression of IDO is upregulated in response to signalling by inflammatory cytokines including interferons (IFN-α, -β, and -γ) and TNF-α 24 . Previously reported cytokine data from this cohort demonstrated elevated levels of IFN-γ and TNF-α 26 . However, in the current study, although quinolinic acid, IFN-γ and TNF-α serum levels were all higher in the burn patients, the correlation between quinolinic acid and these cytokines was weak.…”

“…Of the 36 samples collected, Fifteen female and 18 male burn survivors provided sufficient plasma samples for analysis with three samples not sufficient for further study (n = 33 for analysis). Previous analysis using this cohort showed a diminished immune response in the burn injury survivors in comparison to their healthy uninjured counterparts 26 .…”

Non-severe burn injury increases cancer incidence in mice and has long-term impacts on the activation and function of T cells

“…A study of severely burned children found that cytokines Interleukin 10 (IL-10), Granulocyte-macrophage-colony stimulating factor (GM-CSF), Tumor necrosis factor alpha (TNF-α), IL-2 and IL-17 were significantly elevated up to 3-years post-injury [ 11 ], indicative of a suppressive immune phenotype. A more recent study in non-severe burn paediatric patients [<10% total body surface area (TBSA)] similarly showed sustained increases of TNF-α, IL-2, IL-7 and Interferon gamma (IFN-γ) >3 years post-injury [ 12 ], and analysis of peripheral blood mononuclear cells showed significant increases in myeloid dendritic cells, memory CD4 + T cells and memory T-regulatory cells, providing evidence of long-term alterations in immune cell populations in paediatric burn patients. While similar studies are lacking in adults, the observation that even non-severe burn injury is associated with significantly increased risk and severity of infectious diseases and respiratory infections (determined by both admission rates and length-of-stay in hospital) over a follow-up period of around 15 years post-burn injury [ 6 , 8 ], suggests that immune dysfunction is also likely occurring in the adult burn population.…”