Monitoring of the Forgotten Immune System during Critical Illness—A Narrative Review

Abstract

Immune organ failure is frequent in critical illness independent of its cause and has been acknowledged for a long time. Most patients admitted to the ICU, whether featuring infection, trauma, or other tissue injury, have high levels of alarmins expression in tissues or systemically which then activate innate and adaptive responses. Although necessary, this response is frequently maladaptive and leads to organ dysfunction. In addition, the counter-response aiming to restore homeostasis and repair injury can also be detrimental and contribute to persistent chronic illness. Despite intensive research on this topic in the last 40 years, the immune system is not routinely monitored in critical care units. In this narrative review we will first discuss the inflammatory response after acute illness and the players of maladaptive response, focusing on neutrophils, monocytes, and T cells. We will then go through commonly used biomarkers, like C-reactive protein, procalcitonin and pancreatic stone protein (PSP) and what they monitor. Next, we will discuss the strengths and limitations of flow cytometry and related techniques as an essential tool for more in-depth immune monitoring and end with a presentation of the most promising cell associated markers, namely HLA-DR expression on monocytes, neutrophil expression of CD64 and PD-1 expression on T cells. In sum, immune monitoring critically ill patients is a forgotten and missing piece in the monitoring capacity of intensive care units. New technology, including bed-side equipment and in deep cell phenotyping using emerging multiplexing techniques will likely allow the definition of endotypes and a more personalized care in the future.

PAMPs and DAMPs in Sepsis: A Review of Their Molecular Features and Potential Clinical Implications

“…Immune cells-Many studies have analyzed the PAMPs/DAMPs and receptor expression in the immune cells, mainly in macrophages and neutrophils. For example, iHMGB1 seems to prevent macrophage cell death in bacterial infection by mediating autophagy, whilst eHMGB1 induces cytokine release via the TLR4/MD2/MyD88/NF-κB pathway [75,76]. Moreover, when activating the RAGE pathway, it induces inflammasome and caspase-1 activation with subsequent pyroptosis [22].…”

Hospital-Onset Sepsis Warrants Expanded Investigation and Consideration as a Unique Clinical Entity

“…In addition to observed differences in comorbidities, clinical presentation, complications, and outcomes compared with COS patients, patients who have been hospitalized are susceptible to changes in microbiome, vascular permeability, and immune function that may be important determinants of unique physiologic HOS phenotypes. 37 , 38 , 39 Comprehensive latent clinical phenotypes associated with patterns of organ dysfunction, inflammatory profiles, patient outcomes, and related treatment implications have been described in COS, but equivalent research has lagged for HOS. 40 , 41 , 42 In light of data suggesting heterogeneity of treatment effect across sepsis phenotypes and molecular endotypes—with variable benefit, and at times even harm, from interventions such as aggressive fluid resuscitation and corticosteroids—the identification of clinically important HOS phenotypes and subgroups will be vital to inform strategic enrollment into clinical trials, targeted quality improvement initiatives, and the development of precision treatment approaches.…”

Diagnosis and management of invasive fungal diseases in non-neutropenic ICU patients, with focus on candidiasis and aspergillosis: a comprehensive review

“…However, more importantly, the ICU patient cohort does not fit into “the classical host” described for defining IFD in the scientific literature ( Bassetti et al., 2017 ). ICU patients may show variable grades of alteration in immune response ranging from functional defects to alteration in the subset of cells belonging to innate or adaptive immunity ( Serrano et al., 2023 ). These defects may predispose ICU patients to different forms of invasive fungal infections, but they still do not qualify the classical host criteria of immunocompromised patients.…”