Question

Activity 2.3 Clinical Case Study Scenario A 7-year-old boy with an infected wound on his leg is admitted to the emergency department. His mother states that a high fever with diarrhea occurred during the last 12 hours. Within the last 2 hours he had become very lethargic, was unable to stand, and was very disoriented. The doctor observes that his blood pressure is dangerously low and suspects that the boy is suffering from bacterial septic shock caused by the wound infection.

Discuss the role of cytokines in the pathogenesis of this disease. Speculate on future therapeutic strategies that might be employed by using monoclonal antibodies or other biologic agents to treat this disease.

Answer 1

Cytokines are important pleiotropic regulators of the immune response, which have a crucial role in the complex pathophysiology underlying sepsis. They have both pro- and anti-inflammatory functions and are capable of coordinating effective defense mechanisms against invading pathogens

An initial step in the activation of innate immunity is the de novo synthesis of small polypeptides (cytokines) that induce protean manifestations on most cell types, from immune effector cells to vascular smooth muscle and parenchymal cells. Several cytokines are induced, including tumor necrosis factor (TNF) and interleukins (ILs), especially IL-1. These factors help keep infections localized; however, once the infection progresses, the effects can also be detrimental.

Circulating levels of IL-6 correlate have a strong correlation with outcome. High levels of IL-6 are associated with mortality, but the role of this cytokine in pathogenesis is not clear. IL-8 is an important regulator of neutrophil function, synthesized and released in significant amounts during sepsis. IL-8 contributes to the lung injury and dysfunction of other organs.

Monoclonal antibodies in sepsis

The role of anti-endotoxin antibodies in the management of gram-negative bacteremia and the experimental and clinical studies on the cross-protection afforded by core LPS antibodies are reviewed. These studies did not achieve clarification of the epitope(s) and effector mechanism(s) involved in protection. Recently, two anti-lipid A IgM monoclonal antibodies, designated E5 and HA-1A, have been investigated in patients with gram-negative bacterial infections and clinical manifestations of septicemia. E5 reduced the mortality of patients if they were not in shock, whether they were bacteremic or not. A confirmatory study has been initiated. In contrast to E5, HA-1A protected patients whether they were in shock or not, but only when they were bacteremic at randomization. Although these studies suggest beneficial effects, the type of patients who may benefit from this expensive therapy should be further defined. Further investigations are needed to clarify the mechanisms of protection of these antibodies.