Changes in circulating procalcitonin versus C-reactive protein in predicting evolution of infectious disease in febrile, critically ill patients.

OBJECTIVE: Although absolute values for C-reactive protein (CRP) and procalcitonin (PCT) are well known to predict sepsis in the critically ill, it remains unclear how changes in CRP and PCT compare in predicting evolution of: infectious disease, invasiveness and severity (e.g. development of septic shock, organ failure and non-survival) in response to treatment. The current study attempts to clarify these aspects.
METHODS: In 72 critically ill patients with new onset fever, CRP and PCT were measured on Day 0, 1, 2 and 7 after inclusion, and clinical courses were documented over a week with follow up to Day 28. Infection was microbiologically defined, while septic shock was defined as infection plus shock. The sequential organ failure assessment (SOFA) score was assessed.
RESULTS: From peak at Day 0-2 to Day 7, CRP decreased when (bloodstream) infection and septic shock (Day 0-2) resolved and increased when complications such as a new (bloodstream) infection or septic shock (Day 3-7) supervened. PCT decreased when septic shock resolved and increased when a new bloodstream infection or septic shock supervened. Increased or unchanged SOFA scores were best predicted by PCT increases and Day 7 PCT, in turn, was predictive for 28-day outcome.
CONCLUSION: The data, obtained during ICU-acquired fever and infections, suggest that CRP may be favoured over PCT courses in judging response to antibiotic treatment. PCT, however, may better indicate the risk of complications, such as bloodstream infection, septic shock, organ failure and mortality, and therefore might help deciding on safe discontinuation of antibiotics. The analysis may thus help interpreting current literature and design future studies on guiding antibiotic therapy in the ICU.

Introduction

In critically ill patients, new onset fever often prompts clinicians to search for nosocomial microbial infection and to start empiric antibiotics in attempts to diminish morbidity and mortality [1]–[3]. Plasma levels of C-reactive protein (CRP) or procalcitonin (PCT) are often used to increase the a priori probability of microbial infection and sepsis in the intensive care unit (ICU) [2]–[12]. In a previous study on absolute levels within the first days after new fever onset in critically ill patients, we found that CRP may particularly help in predicting local microbial infection and PCT in predicting bloodstream infection (BSI) and a downhill clinical course [3]. The clinical relevance of changes in the markers is less clear, however. Changes in CRP and PCT over 2–7 days have been described in non-critically ill patient populations [13]–[20], in relatively small studies, about 50 patients or less [4], [9], [13], [15], [16], [19], [21]–[25], in specific conditions [2], [8], [10], [13], [15]–[17], [19], [20], [22], [24], [26]–[29] or in heterogeneous conditions in the ICU [4]–[7], [9], [11], [21], [23], [30]–[32], to judge the course of infection and its sequelae. CRP decreases of more than about 25% per day within the first week of treatment of (bloodstream) infections or sepsis have been suggested to help predict a beneficial response and disease course, while slower decreases or increases have been associated with persistent infection, organ failure or mortality, also in the ICU [7,8,11,17-19,21-,23,26-29,32]. A relatively rapid fall of PCT may be associated with a beneficial outcome of pneumonia, meningitis, burn-associated or other infections, whereas a rise may be associated with organ failure and mortality and thus might have predictive value (5,6,8–10,15,16,20,24,26,27,30,31]. A fall in PCT below 0.5 ng/mL, a threshold suggested in studies on non-critically ill patients, has been used to safely and effectively shorten the duration of administration of antibiotics for infections in the ICU [33]. CRP and PCT changes have been compared in their relative ability to detect the evolution of infection or sepsis, within [4]–[6], [10], [24]–[27], [30], [31] or outside the ICU [8], [14], [15], [18], [19]. CRP may display slower kinetics than PCT and in some, but not all studies, decreases or increases of the latter may better predict a beneficial or downhill course with resolving or aggravating organ failure, respectively [2], [4], [6], [8], [10], [14]–[16], [19], [24]–[27], [30], [31], [34]. Nevertheless, the relative value of marker changes in predicting response to antibiotic treatment of ICU-acquired infections is only rarely addressed [10], [15], [24], [26], [27], [31]. Hence, general conclusions on the relative superiority of the markers for specific endpoints in the critically ill are hard to draw from the literature and the controversy is ongoing.

In order to further help clinical decision making on the basis of changes in CRP and PCT in the ICU, we hypothesized for the current study that, in general critically ill patients with new onset fever, the 1-week course of CRP and PCT levels can be used to distinguish resolving microbial infection with a beneficial outcome from non-resolving or developing infection with a detrimental outcome associated with BSI, septic shock, organ failure and death. We also hypothesized that CRP and PCT differ in this respect, so that CRP primarily predicts the course of local infection and PCT that of systemic infection and its adverse sequelae. This would also help to define values at which antibiotic treatment can be decided as appropriate or to allow safe discontinuation in the ICU.

Materials and Methods

This is a prospective observational study on causes and consequences of ICU-acquired fever, approved by the medical ethical committee of the VU University Medical Center, Amsterdam, conducted between 2003 and 2007. All patients or closest relatives gave their written informed consent, leading to inclusion of 101 consecutive patients with new onset fever, admitted to a mixed medical/surgical ICU, and the complete protocol has been described elsewhere [3]. The current analysis is on the 72 patients having completed a follow up of at least 7 days in the ICU (Consort diagram Figure S1). To briefly reiterate, a body temperature >38.3°C measured rectally was the main inclusion criterion, while admitted to the ICU for at least 24 hours without fever (body temperature <37.5°C). Exclusion criteria were: age under 18 years, pregnancy and life expectancy of <24 hours. Enrolment had to be completed within 12 hours of meeting inclusion criteria and was marked Day 0 (D0). Demographic data were collected. Disease severity was expressed through the simplified acute physiology scores (SAPS) II and monitored using sequential organ failures assessment (SOFA)-scores. On Days (D) 0, 1, 2 and 7 clinical data were recorded and blood was drawn for determination of routine parameters and markers. Antibiotic treatment and changes within the study period were recorded.

Routine chest- and sinus-radiographs were taken on D0 and 7, all other diagnostic imaging were ordered by treating physicians, blinded to results, as considered necessary. Blood samples for microbiological culture were taken from indwelling arterial catheters using delayed vial entry bottles for aerobic and anaerobic cultures and processed according to protocol. Depending on suspicion of local infection, specimens for microbial culture were collected. Investigation of fungal, viral or atypical microorganisms was left at the treating physician’s discretion. All culture and staining results from specimens drawn between D0–7 were evaluated. Positive cultures considered to represent colonization were not considered to represent infection and microorganisms are grouped according to genus. The presence of infection was determined by researchers (SHH and ABJG) blinded to study results and classified by likelihood into possible, probable or proven infection, according to criteria defined at the International Sepsis Forum Consensus Conference [35]. Infections are only considered when probable or proven [3]. Sepsis was defined as infection in the presence systemic inflammatory response syndrome (SIRS) criteria, according to ACCP/SCCM (American Society of Chest Physicians/Society of Critical Care Medicine) [36]. Criteria of shock criteria were a systolic arterial pressure <90 mmHg or a mean arterial pressure (MAP) <70 mmHg for at least one hour, despite fluid resuscitation, or need of vasopressor treatment. Shock in the presence of sepsis was marked septic shock. Organ failure was assessed by the sequential organ failure assessment (SOFA) score on Day 0, 1, 2 and 7.

Patients were divided into four categories of infectious course: Group 1 with infection presenting at D0–2 and without evidence of infection at D3–7, thus having a response to treatment and resolving infection, Group 2 with infection presenting D0–2 and persisting positive cultures from the same infection site and/or persisting positive cultures with the same microorganism at D3–7, thus having treatment failure, Group 3 without infection D0–2 and with infection D3–7, thus having a new infection, and Group 4 without infection D0–2 and D3–7. Complications of infection were considered BSI, septic shock and outcome. Therefore a similar division was done for BSI, irrespective of local cultures. Group 1a with BSI presenting D0–2 and without BSI D3–7, thus resolving BSI in response to treatment. Group 2a with BSI presenting D0–2 and with persisting BSI D3–7, i.e. treatment failure, Group 3a without BSI D0–2 and with infection D3–7, having a new BSI and Group 4a without BSI D0–2 and D3–7. Septic shock was defined by the presence of shock within 12 hours prior or 12 hours after the determination of infection in either one of the respective study intervals. Group 1b represents presence of septic shock in D0–2 but without septic shock in D3–7, Group 2b presents septic shock both in D0–2 and D3–7, Group 3b absence of septic shock in D0–2 but presence of septic shock D3–7, and Group 4b absence of septic shock in both study intervals. Analogously, we divided patients with decreasing SOFA scores (peak D0–2 to 7; Group 1c), unchanged SOFA scores (Group 2c) and increasing SOFA scores (Group 3c). Outcome is 28-day survival or all-cause mortality.

Routine parameters measured were white blood cell count (WBC) (Sysmex SE-9000 analyzer, Toa Medical Instruments, Kobe, Japan, normal values 4.5–10 x109/L), lactate (Enzymatic method, Modular analytics