Fever and Leukocytosis

Fever is defined as an elevated core body temperature albeit with no consensus as to the specific threshold temperature that qualifies as a fever. For example, the Centers for Disease Control and Prevention (CDC) uses  > 100° F for a fever in its case definition of influenza and > 101° F ( > 38.0° C) for the purposes of surveillance for health care–associated infections (HAIs) (nosocomial infections). Fever is caused by the release of cytokines (so-called endogenous pyrogens, e.g., IL1) in response to injury, inflammation, antigenic challenge, or infection. Thus, fever itself cannot reliably distinguish infectious from noninfectious causes. Despite its seemingly common occurrence, few prospective data exist on the frequency and causes of fever specifically in ICU patients. A small prospective study in adult ICU patients published in 1999 showed that fever occurred in 70% of ICU admissions but was associated with infection in only 53% of cases, confirming that fever is not a specific marker for infection. Furthermore, fever has been found to be present in only half the cases of sepsis and postoperative infections, indicating that it is also not a sensitive marker for infection in these populations.

In non-ICU studies, many hospitalized patients with fever but no clinical evidence for infection received antibiotics, suggesting that much of the antibiotic use in non-ICU patients that is initiated for fevers alone is unnecessary and can be eliminated without jeopardizing patient care. By inference, starting antibiotics for fever alone in ICU patients is inappropriate (with the exception of patients with neutropenia [see Chapter 24]), and the presence of fever should instead stimulate a systematic search for its cause (see Chapters 13 and 14).

Like fever, leukocytosis (elevated white blood cell [WBC] count, specifically WBC > 15,000 cells/μL) also has a low specificity. Although such a degree of leukocytosis is associated with an increased risk of bacterial infection, almost half of such patients have no identifiable infection.

Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and Septic Shock

The systemic inflammatory response syndrome (SIRS) is defined as the simultaneous presence of two or more physiologic signs that can result from systemic inflammation: (1) fever (or hypothermia), (2) tachycardia, (3) tachypnea, and (4) a neutrophilic leukocytosis. SIRS can arise from infectious or noninfectious causes. Sepsis has been defined as SIRS with clinical evidence (or high suspicion) of infection. Severe sepsis refers to the clinical situation of sepsis with evidence of (otherwise unexplained) inadequate end organ perfusion. Septic shock is severe sepsis with clinically significant hypotension (see Chapter 10). Even though infection is common in patients with severe sepsis (present in ~90% of patients in one large prospective epidemiologic study), bloodstream infection (bacteremia or fungemia) was documented in only about one quarter of this group of patients overall.

Despite the above-mentioned limitations of using fever, leukocytosis, and SIRS/sepsis as markers of infections, these signs are still clinically important and their presence should always prompt a thorough search for their cause (see Chapters 10, 13, and 14).

An additional complexity of diagnosing infection in ICU patients is that even objective clinical data, such as microbiologic cultures, can often be confusing. For example, a positive culture of sputum or a tracheal aspirate for a pathogenic organism does not necessarily prove the presence of a health care–associated pneumonia or even tracheobronchitis. Likewise, a negative culture—for example, a tracheal aspirate sent the day after the start of new antimicrobials—does not confirm the absence of infection. Finally, some culture results may be uninterpretable because of an ill-considered approach to the diagnostic evaluation, such as relying exclusively on blood cultures obtained from existing central venous catheters without the benefit of cultures drawn from a peripheral site. This can complicate the interpretation of cultures growing common skin contaminants such as coagulase-negative Staphylococcus species (see Chapter 14).

A final consideration when selecting an appropriate empirical antibiotic regimen is an appreciation of the epidemiology of common health care–associated infections within one’s own ICU and hospital. Rates of health care–associated infections among ICU admissions range from 3% to 31% and can vary between community and university hospitals as well as between different types of ICUs within the same hospital. Likewise, the prevalence of specific pathogens and their antimicrobial resistance patterns can vary considerably among different hospitals, ICU types, and even over time within the same ICU. Understanding one’s local epidemiology is crucial for selecting a regimen that provides adequate antimicrobial coverage for the most likely infecting pathogens while also minimizing the risk of promoting antimicrobial resistance with agents that have too broad a spectrum of coverage.