Abstract
Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis.
Highlights
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1]
This review highlights the current challenges we face toward precision immunotherapy for patients suffering from sepsis
The urgent need for a patient-tailored approach in sepsis treatment is clear, as 40 years of undirected sepsis trials have not resulted in a single adjunctive therapy in current clinical use
Summary
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. To the best of our knowledge, this is currently unknown and a multifactorial etiology is likely, including hostrelated factors such as age, gender, comorbidities, (epi)genetic predisposition, microbiome composition, expression levels of pattern-recognition receptors (PRRs), and release of DAMPs as well as pathogen-related factors such as the type of pathogen, its virulence and load, and quorum sensing Whether it concerns hyperinflammation or immunoparalysis, it appears implausible that a single marker can act as a reliable tool to guide immunomodulating therapy since biomarkers are often related to one or a limited number of pathophysiological mechanisms/pathways, while it has become clear that multiple pathways are activated or inhibited at the same time in sepsis.
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