Immunomodulatory therapy for sepsis: an update

Abstract

Currently the treatment mainstay of sepsis is early and appropriate antibiotic therapy, accompanied by aggressive fluid administration, the use of vasopressors when needed and the prompt initiation of measures to support each failing organ. Activated protein C and hydrocortisone, when used accordingly can affect mortality. As the pathophysiologic events that take place during sepsis are being elucidated, new molecules that target each step of those pathways are being tested. However, a lot of those molecules affect various mediators of the sepsis cascade including inflammatory cytokines, cellular receptors, nuclear transcription factors, coagulation activators and apoptosis regulators. Over the last decade, a multitude of clinical trials and animal studies have investigated strategies that aimed to restore immune homeostasis either by reducing inflammation or by stimulating the innate and adaptive immune responses. Antibiotics, statins and other molecules with multipotent immunomodulatory actions have also been studied in the treatment of sepsis.

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“…Rodents and humans respond differently to infectious agents and possess disparate inflammatory responses (Leist and Hartung, 2013;Tuomela and Lahesmaa, 2013). By 2011, N 100 clinical trials testing anti-inflammatory drugs that were effective in rodents had failed in humans (Rice, 2012;Christaki et al, 2011). Typically, b50% of genes shown to be differentially regulated in rodent models of immune response (endotoxemia, trauma, and burn) are found to change expression in humans exposed to the same inflammatory conditions (Seok et al, 2013).…”

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“…This situation did not become better with more time for trials and optimization of animal studies (Buras et al, 2005). When the only treatment discovered by this approach, activated C-reactive protein, had to be withdrawn from the market in 2011, more than 100 additional clinical trials had been performed, and it became evident that every single approach that had been successful in animals had failed (Rittirsch et al, 2007;Christaki et al, 2011). Nevertheless, animal-based studies in this field still continue to be financed.…”

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“…Note that this spectacular failures and unexpected toxicities." Opal updated these data for 2009 in his presentation to the committee reporting that 42 clinical studies led to 39 cases of lack of effect, one small effect, and two cases where the situation of the patients worsened (Christaki et al, 2011).…”