Background
Sepsis is a leading cause of mortality and critical illness worldwide [
1]. Recent reports have shown that patient mortality has been reduced, particularly when recommended bundles of care are applied [
2,
3]. Nevertheless, the septic shock mortality rate still varies between 30 and 40% [
2,
3]. In accordance with recent findings, there is growing interest in long-term sepsis outcomes. Sepsis is associated with an increased mortality rate in the months and years after hospital discharge [
4]. Observational studies have reported 1-year mortality rates greater than 50% after hospital discharge [
5]. The consequences of sepsis, therefore, are not limited to those observed during ICU stays. Post sepsis, patients are prone to decompensating or experiencing several diseases or organ dysfunction, such as cardiovascular disease [
6‐
8], pulmonary disease [
9], renal disease [
10], depression and cognitive disabilities [
11], and immune dysfunction [
12]. These ailments lead to long-term decreased functional status [
13]. The occurrence of persistent or new organ(s) dysfunction(s) after septic shock raises questions about the cellular, metabolic and immune mechanisms involved in the post-sepsis status.
Potential mechanisms that alter long-term outcomes, such as persistence of altered innate immune and pro-coagulant responses to sepsis, have been previously described. These mechanisms have been studied through several mediators or molecules, such as C-reactive protein (CRP), tumor necrosis factor (TNFα), interleukin (IL)-6, IL-10, d-dimers, antithrombin-III, and factor IX, and the fibrinolytic pathway [
12,
14‐
16]. Another mechanism is the altered adaptive immune response, with depletion of naïve immune cells [
17]. Beside usual mediators like inflammatory cytokines, lipid mediators, and protein from the apoptosis cell death machinery, there is growing interest in metabolites involved in inflammation. Tryptophan (Trp) and its metabolites play an important role in the immune balance between response to pathogen and tolerance [
18].
The underlying mechanisms explaining the impact of the ICU stay on post-ICU outcomes remain unclear. Accordingly, the present study aimed to explore the natural evolution of the immune profile from ICU admission to 1 year later and to assess the relationship between this immune profile and 1e-year outcomes in ICU patients admitted with abdominal septic shock.
Discussion
This study aimed to explore the evolution of the immune profile of patients admitted to the ICU for septic shock of abdominal origin up to 1 year after ICU discharge. Thus, we studied several plasma biomarkers at ICU admission, discharge and 12 months after ICU discharge. The primary result was a protracted immune disturbance 1 year after ICU discharge, Several markers had persistent abnormal levels; IL-6, Trp, Kyn and IDO in cluster 1, caspase 3 in cluster 2, and PD-1 and IL-7 in cluster 3 were significantly elevated. The proportion of patients having at least one abnormal biomarker in only one cluster was 9% (n = 4), whereas 70% (n = 32) had abnormal values of biomarkers within all three clusters.
The study of the variations from ICU discharge to 1 year identified two types of biomarkers of change: those associated with a significant decrease (i.e., PD-1, RvD5, IL-6, caspase 3, IL-10, IL-17 and INF-γ) and those associated with no significant change from discharge to 1 year (i.e., Kyn, IDO, HMGB1, uric acid, TNFα, Trp, IL-7, and RvD1).
We also explored the relationship between the biomarker levels and patient outcomes. At admission, the patients who died in the ICU had higher levels of inflammatory biomarkers (IL-17, Kyn, IDO) and cell damage biomarkers (HMGB1, caspase 3), while levels of IL-10, an anti-inflammatory cytokine, were lower compared to levels in the survivors. At ICU discharge, HMGB1 was higher and RvD5 was lower in the patients who died in the first year after sepsis compared to the survivors. These results highlight the long-term sequelae of septic insult.
It is now well-recognized that patients with sepsis continue to have the worst outcomes in the months and years after hospital discharge; there is growing interest in the study of long-term sepsis outcomes. Several reports have shown that sepsis survivors are likely to develop chronic illness, such as cardiovascular [
8], pulmonary [
9], and renal [
10] disease, or depression [
11]. Our study findings align with those of prior studies. Persistent inflammation, with elevated levels of IL-6 and IL-10, was found at hospital discharge after community-acquired pneumonia [
12].
Little is known about the disease mechanistic pathways involved in this phenomenon. To explore this pathogenesis, we conducted a wide study of the immune profile over time. We did not limit our work to inflammation but extended it to the markers of cell damage, apoptosis, immunosuppression and resolution of inflammation, to paint a picture of an evolving mechanism beginning with tissue damage that causes inflammation, followed by a healing process to restore homeostasis.
There is a discrepancy between the clinical picture of “cured” patients who are eligible for ICU discharge (for whom dampening of the inflammation is expected to be rather quick) and evidence of persistent sickness with a damaged immune response that remains long after the event. This discrepancy emphasizes the absence of a homeostasis reset after curing visible signs of sepsis, which could lead to the development or acceleration of chronic diseases.
Most of the studied markers tended to return (more or less) to their normal levels. The clinical significance of moderately elevated IL-6, Kyn, and IDO is questionable. In addition, long-term mild inflammation has been associated with bad outcomes in various diseases, such as cancer [
27] or atherosclerosis [
28]. Trp and its metabolites play an important role in the immune balance between response to pathogen and tolerance [
18]. Trp, an essential amino-acid, is the serotonin precursor and Trp deficits are correlated with impaired T cell proliferation [
29] and enhancement of cellular stress response. The intracellular enzyme, IDO degrades Trp and produces Kyn-derived metabolites. IDO is stimulated by lipopolysaccharide (LPS), TNFα, IFN-γ, transforming growth factor (TGF)ß and activation of toll-like receptor (TLR)3, TLR4, TLR7, and TLR8 [
30]. After major trauma, increased plasma Kyn and Kyn-Trp ratios are early indicators for sepsis development [
31]. Kyn directly damages tissues and organs, induces dysregulation of vascular tone, and is a key factor in the communication between the nervous and immune systems. Kyn metabolites such as kynurenic and quinolinic acids could also impair neurological systems [
32].
Trp levels increased from ICU discharge to 1 year, and while this increase is supposed to be beneficial, the levels remained below the control group values at 1 year. Low Trp levels are reportedly associated with cancer [
33], cardiovascular disease [
34], and depression [
35]. Integrative studies using several immuno-metabolic markers and clinical score were found to be useful to predict the risk but could also help in the understanding of the pathophysiology of septic derangements [
36,
37]. PD-1, which has an immunosuppressive function as a negative regulator of T cells by preventing their proliferation and altering their bacterial clearance, was still elevated at 1 year, although this biomarker level dramatically decreased (80%) after ICU discharge. Together, these findings raise the hypothesis of a protracted immunodeficiency state.
The elevated levels of IL-7 were surprising. This report is the first to focus on circulating IL-7 at 1 year after septic shock and indicates an ongoing immune process. IL-7 is thought to be a beneficial mediator after acute inflammation. It has an anti-apoptotic effect on lymphocytes and has stimulating effects on B lymphocytes and natural killer cells [
38]. These findings raise the question of a lasting immune healing response and may indicate a possible treatment for post-sepsis immune dysfunction, because IL-7 administration has already been proposed for immune depression in HIV infection [
39]. The effect of IL-7 on long-term outcomes must be further investigated.
Limitations of the study
Our cohort was monocentric and relatively small, in terms of the high number of studied biomarkers. It is, therefore, possible that some of our conclusions are erroneous and must be confirmed in larger prospective multicentric studies. We also studied a specific group of patients (i.e., those with septic shock of abdominal origin), which limits the generalizability of our results. The choice of patients with septic shock and not patients with severe sepsis was based on the hypothesis that the sickest patients have worse symptoms and would be more easily identified among a limited number of subjects. We had to choose a limited number of biomarkers. We cannot exclude that other molecules could have been of interest. In addition, we did not study cell function or number at 1 year. Our study was focused on the variation of the biomarkers levels during and after ICU admission and discharge. The association between the biomarkers levels and prognosis was a secondary objective and therefore no sample calculation was made. Conclusions that can be drawn from these data are limited.
Source control may impact the kinetics of the measured mediators. All our patients had the same type of source control (i.e., surgery). Despite the fact that the time and type of surgery could play a role in patient disease severity, we believe that they would marginally impact the levels of mediators at the studied time points. More important, we do not have any data on the relationships between the biomarker levels and outcomes other than death. Such data were, unfortunately, not recorded. The control group was not matched on age, sex, and comorbidities, limiting the interpretation of the results. Another limitation is that we could not assess the levels of biomarkers in our patients before they had septic shock; these could have been abnormal before the onset of sepsis. There is a long gap between ICU discharge and 1 year. The exclusion of nine patients who died during this period may bias the results. If measurements were obtained at 3 and 6 months, more abnormalities may have been detected.