Diagnosis of Infection in Critical Care

Belén Prieto*; Francisco V. Álvarez Menéndez*,†,1    * Clinical Biochemistry, Laboratory of Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
† Biochemistry and Molecular Biology Department, University of Oviedo, Oviedo, Spain
1 Corresponding author: email address: falvarezmen@gmail.com

1 Background

Sepsis is the primary cause of death in the intensive care unit (ICU). Early antibiotic therapy plays a crucial role on the prognosis of these patients. The prevention of sepsis complications requires an early and accurate diagnosis as well as the appropriate monitoring. At present, most microbiological laboratories are limited by poor sensitivity and the time-consuming nature of culture-based methods. The clinical symptoms of the septic patient are often masked by systemic inflammatory response processes, infectious or not, and treatments. The diagnostic difficulty of sepsis is even more relevant in both pediatric and adult ICUs, where patients are at increased risk because of not only their critical state and immunological vulnerability but also the use of invasive techniques (e.g., mechanical ventilation) and nonspecific symptoms. Moreover, the preventive administration of antibiotics in critical care patients increases resistance and the risk of hospital-acquired infections. On the other hand, time factor also plays an important role in the prognosis of sepsis, since a delay in the identification and appropriate management of critical patients during the first 6 h of admission to the ICU is associated with higher mortality [1].

The concept of systemic inflammatory response syndrome (SIRS) was established for the first time at the Sepsis Consensus Conference held in 1992 by the Society of Critical Care Medicine and the American College of Chest Physicians [2]. Since then, SIRS has been defined according to well-established criteria (Table 2.1), without the need for the demonstration of the presence of bacterial infection by microbiological culture, whereas sepsis is considered as a SIRS in response to documented infection that can lead to severe consequences, including multiple organ failure.

Other stages of sepsis were also defined, such as severe sepsis, associated with organ dysfunction, hypoperfusion or hypotension, and septic shock, the most severe stage of sepsis, cursing with arterial hypotension despite adequate fluid resuscitation.

The differentiation between infectious SIRS and other etiologies, as well as the stratification of the disease progression in these three stages, is very important, since their management and evolution are quite different [3].

However, the clinical application of these definitions quickly demonstrated that they lacked sufficient diagnostic efficiency. The presence of clinical signs of inflammation is shown in both infectious and noninfectious processes, microbiological culture being the reference differential diagnostic tool. The development of new biochemical markers of inflammation, such as C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6), improved the differentiation of both clinical situations, thus allowing the redefinition of SIRS and sepsis in the International Sepsis Definition Conference in 2001 [4]. By this time, a new staging system was established, named PIRO system (from Predisposition, Infection, Response, and Organ Dysfunction) aimed at stratifying patients based on not only the clinical features but also the biochemical markers of inflammation (Fig. 2.1; Ref. [5]).

From a more clinical perspective, it has been recently proposed to include evidence of organ dysfunction in the criteria for sepsis [6]. Of note, this slightly differs from the definition used in the recently published guidelines of the Surviving Sepsis Campaign in which sepsis is defined clinically as the presence (probable or documented) of infection together with systemic manifestations of infection and severe sepsis is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion [7].

Despite the great advance in our knowledge on the pathogenesis of sepsis, severe sepsis, defined as sepsis with organ failure, remains associated with an unacceptable high mortality [8].

2 Immunologic Basis of Sepsis

The inflammatory process starts as a response mediated by cellular and humoral factors that seek to limit, eliminate, and repair the lesion caused by the infectious agent. This inflammatory response is sometimes exaggerated and not limited only to the lesion point, thus spreading to the entire organism and leading to a SIRS.

Activating agents, infectious or not, will be recognized by immune system cells by surface receptors (Fig. 2.2; Ref. [9]). SIRS begins with a rapid release of proinflammatory cytokines (IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-15, IL-18, and α-tumoral necrosis factor or TNF-α), as well as immunological cytokines, γ-interferon, and TNF-β. Liberation of proinflammatory cytokines is very fast, and they are rapidly cleared from systemic circulation. TNF-α plays a central role in the pathogenesis of SIRS: it is released into peripheral blood...