Eric S. Nylen

Procalcitonin assay in systemic inflammation, infection, and sepsis : Clinical utility and limitations

Objective:The use of procalcitonin (ProCT) as a marker of several clinical conditions, in particular, systemic inflammation, infection, and sepsis, will be clarified, and its current limitations will be delineated. In particular, the need for a more sensitive assay will be emphasized. For these purposes, the medical literature comprising clinical studies pertaining to the measurement of serum ProCT in various clinical settings was examined. Data Source and Selection:A PubMed search (1965 through November 2007) was conducted, including manual cross-referencing. Pertinent complete publications were obtained using the MeSH terms procalcitonin, C-reactive protein, sepsis, and biological markers. Textbook chapters were also read and extracted. Data Extraction and Synthesis:Available clinical and other patient data from these sources were reviewed, including any data relating to precipitating factors, clinical findings, associated illnesses, and patient outcome. Published data concerning sensitivity, specificity, and reproducibility of ProCT assays were reviewed. Conclusions:Based on available data, the measurement of serum ProCT has definite utility as a marker of severe systemic inflammation, infection, and sepsis. However, publications concerning its diagnostic and prognostic utility are contradictory. In addition, patient characteristics and clinical settings vary markedly, and the data have been difficult to interpret and often extrapolated inappropriately to clinical usage. Furthermore, attempts at meta-analyses are greatly compromised by the divergent circumstances of reported studies and by the sparsity and different timing of the ProCT assays. Although a high ProCT commonly occurs in infection, it is also elevated in some noninfectious conditions. Thus, the test is not a specific indicator of either infection or sepsis. Moreover, in any individual patient, the precipitating cause of an illness, the clinical milieu, and complicating conditions may render tenuous any reliable estimations of severity or prognosis. It also is apparent that even a febrile septic patient with documented bacteremia may not necessarily have a serum ProCT that is elevated above the limit of functional sensitivity of the assay. In this regard, the most commonly applied assay (i.e., LUMItest) is insufficiently sensitive to detect potentially important mild elevations or trends. Clinical studies with a more sensitive ProCT assay that is capable of rapid and practicable day-to-day monitoring are needed and shortly may be available. In addition, investigations showing that ProCT and its related peptides may have mediator relevance point to the need for evaluating therapeutic countermeasures and studying the pathophysiologic effect of hyperprocalcitonemia in serious infection and sepsis.

Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis.

OBJECTIVES Procalcitonin (ProCT), the precursor to the calcitonin hormone, is abnormally increased in experimental and clinical systemic inflammation, including sepsis. Initially, we investigated the effects of supraphysiologic amounts of ProCT administered to animals with septic peritonitis. Subsequently, we evaluated the efficacy of prophylactic and therapeutic immune blockade of ProCT in this lethal model of sepsis. DESIGN Prospective, experimental, controlled study. SETTING Animal research laboratory approved by the American Association for the Accreditation of Laboratory Animal Care at a Veterans Affairs Medical Center. SUBJECTS Young male Golden Syrian hamsters, weighing 90 to 120 g. INTERVENTIONS In the first study, serum ProCT concentrations were measured in animals at 0, 3, 6, 12, and 24 hrs after induction of sepsis by intraperitoneal implantation of pellets containing Escherichia coli (5 x 10(8) colony-forming units/pellet). In the second study, with mortality as the end point, 30 microg/kg of isolated, purified human ProCT in 10% hamster serum (experimental) or an equal volume of 10% hamster serum (control) were administered intravenously at the time of the E. coli peritoneal implantation. In the third study, experimental animals received intraperitoneal injections of a multiregion-specific goat antiserum reactive to hamster ProCT 1 hr before and 24 hrs after E. coli implantation, while control animals received nonimmune goat serum at the same time points. In the final study, the same antiserum was administered in five divided doses during the 24 hrs after the insertion of E. coli. MEASUREMENTS AND MAIN RESULTS In the initial study, ProCT concentrations were increased shortly after induction of sepsis and peaked at 12 hrs. Administration of exogenous ProCT to septic animals significantly increased mortality compared with control animals (93% vs. 43%, p=.02). Prophylactic blockade of ProCT almost completely protected the animals from the lethal effects of sepsis: the 102-hr mortality rate in the experimental group was 6% compared with 62% in the control group (p < .003). In the therapeutic trial, the 102-hr mortality rate was 54% in experimental animals compared with 82% in control animals (p < .045). CONCLUSIONS These results demonstrate that increased ProCT exacerbates mortality in experimental sepsis, whereas neutralization of ProCT increases survival. Thus, ProCT, in addition to being an important marker of severity of systemic inflammation and mortality, is an integral part of the inflammatory process and directly affects the outcome.

Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target

The worldwide yearly mortality from sepsis is substantial, greater than that of cancer of the lung and breast combined. Moreover, its incidence is increasing, and its response to therapy has not appreciably improved. In this condition, the secretion of procalcitonin (ProCT), the prohormone of calcitonin, is augmented greatly, attaining levels up to thousands of fold of normal. This hypersecretion emanates from multiple tissues throughout the body that are not traditionally viewed as being endocrine. The serum values of ProCT correlate with the severity of sepsis; they recede with its improvement and worsen with exacerbation. Accordingly, as highlighted in this review, serum ProCT has become useful as a biomarker to assist in the diagnosis of sepsis, as well as related infectious or inflammatory conditions. It is also a useful monitor of the clinical course and prognosis, and sensitive and specific assays have been developed for its measurement. Moreover, it has been demonstrated that the administration of ProCT to septic animals greatly increases mortality, and several toxic effects of ProCT have been elucidated by in vitro experimental studies. Antibodies have been developed that neutralize the harmful effects of ProCT, and their use markedly decreases the symptomatology and mortality of animals that harbour a highly virulent sepsis analogous to that occurring in humans. This therapy is facilitated by the long duration of serum ProCT elevation, which allows for a broad window of therapeutic opportunity. An experimental groundwork has been established that suggests a potential applicability of such therapy in septic humans.

Procalcitonin in Young Febrile Infants for the Detection of Serious Bacterial Infections

OBJECTIVES. The objectives of the study were (1) to study the test performance of procalcitonin for identifying serious bacterial infections in febrile infants ≤90 days of age without an identifiable bacterial source and (2) to determine an optimal cutoff value to identify infants at low risk for serious bacterial infections. METHODS. A prospective observational study was performed with febrile infants ≤90 days of age presenting to an urban, pediatric, emergency department. Serum procalcitonin levels were measured by using an automated high-sensitivity assay. An optimal procalcitonin cutoff value was selected to maximize sensitivity and negative predictive value for the detection of serious bacterial infections. Infants were classified as having definite, possible, or no serious bacterial infections. RESULTS. A total of 234 infants (median age: 51 days) were studied. Thirty infants (12.8%) had definite serious bacterial infections (bacteremia: n = 4; bacteremia with urinary tract infections: n = 2; urinary tract infections: n = 24), and 12 infants (5.1%) had possible serious bacterial infections (pneumonia: n = 5; urinary tract infections: n = 7). Mean procalcitonin levels for definite serious bacterial infections (2.21 ± 3.9 ng/mL) and definite plus possible serious bacterial infections (2.48 ± 4.6 ng/mL) were significantly higher than that for no serious bacterial infection (0.38 ± 1.0 ng/mL). The area under the receiver operating characteristic curve was 0.82 for definite serious bacterial infections and 0.76 for definite and possible serious bacterial infections. For identifying definite and possible serious bacterial infections, a cutoff value of 0.12 ng/mL had sensitivity of 95.2%, specificity of 25.5%, negative predictive value of 96.1%, and negative likelihood ratio of 0.19; all cases of bacteremia were identified accurately with this cutoff value. CONCLUSIONS. Procalcitonin has favorable test characteristics for detecting serious bacterial infections in young febrile infants. Procalcitonin measurements performed especially well in detecting the most serious occult infections.

Exercise Capacity and All-Cause Mortality in African American and Caucasian Men With Type 2 Diabetes

OBJECTIVE The purpose of this study was to assess the association between exercise capacity and mortality in African Americans and Caucasians with type 2 diabetes and to explore racial differences regarding this relationship. RESEARCH DESIGN AND METHODS African American (n = 1,703; aged 60 ± 10 years) and Caucasian (n = 1,445; aged 62 ± 10 years) men with type 2 diabetes completed a maximal exercise test between 1986 and 2007 at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California. Three fitness categories were established (low-, moderate-, and high-fit) based on peak METs achieved. Subjects were followed for all-cause mortality for 7.3 ± 4.7 years. RESULTS The adjusted mortality risk was 23% higher in African Americans than in Caucasians (hazard ratio 1.23 [95% CI 1.1–1.4]). A graded reduction in mortality risk was noted with increased exercise capacity for both races. There was a significant interaction between race and METs (P < 0.001) and among race and fitness categories (P < 0.001). The association was stronger for Caucasians. Each 1-MET increase in exercise capacity yielded a 19% lower risk for Caucasians and 14% for African Americans (P < 0.001). Similarly, the risk was 43% lower (0.57 [0.44–0.73]) for moderate-fit and 67% lower (0.33 [0.22–0.48]) for high-fit Caucasians. The comparable reductions in African Americans were 34% (0.66 [0.55–0.80]) and 46% (0.54 [0.39–0.73]), respectively. CONCLUSIONS Exercise capacity is a strong predictor of all-cause mortality in African American and Caucasian men with type 2 diabetes. The exercise capacity-related reduction in mortality appears to be stronger and more graded for Caucasians than for African Americans.

Disordered calcium homeostasis of sepsis: association with calcitonin precursors

Hypocalcemia and increased serum levels of calcitonin precursors are common in critically ill patients, especially in those with sepsis. We investigated calcium homeostasis in such patients.

Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children.

Objective: Children with cancer often develop febrile illnesses after cytotoxic chemotherapy. Determining which children have serious bacterial infections in this vulnerable period would be valuable. We evaluated the ability of a rapid and sensitive assay for the concentration of calcitonin precursors (CTpr) as a sensitive diagnostic marker for bacterial sepsis in febrile, neutropenic children and determined the utility of measuring cytokines to improve the predictive value of this approach. Design: Prospective cohort study. Setting: Academic children’s hospital. Patients: Fifty-six children (aged 5 months to 17 yrs) with a known malignancy who presented with fever and neutropenia. Interventions: Serial blood samples were obtained (admission, 24 hrs, and 48 hrs), and concentrations of CTpr, interleukin-6, and interleukin-8 were determined. Demographic and laboratory data from the patients were collected from the medical record. Measurements and Main Results: Sixteen (29%) of the children met the criteria for bacterial sepsis. Plasma levels of CTpr and interleukin-8, but not interleukin-6, were increased at all time points in children with sepsis compared with those without sepsis. CTpr at 24 and 48 hrs after admission were reliable markers for sepsis (area under the curve = 0.92 and 0.908, respectively). Logistic regression using CTpr at 24 hrs in addition to interleukin-8 at 48 hrs produced the best-fit models associated with sepsis. Using cutoff values of CTpr >500 pg/mL and interleukin-8 >20 pg/mL produced a screening test for sepsis with 94% sensitivity and 90% specificity. Conclusions: Our data show the utility of a rapid and sensitive assay for CTpr combined with interleukin-8 as a highly sensitive and specific diagnostic marker of bacterial sepsis in febrile, neutropenic children. The use of these markers as a clinical tool may allow for better prognostication for clinicians and may eventually lead to more targeted therapies for this heterogeneous population.

Effect of classic heatstroke on serum procalcitonin.

OBJECTIVE Procalcitonin, the precursor peptide of calcitonin, has been shown to be a serum marker of the severity and mortality of several systemic inflammatory response syndromes. This study addressed the correlation of serum procalcitonin with the course of classic (nonexertional) heatstroke. DESIGN Serum samples were collected prospectively every 6 hrs for 24 hrs. SETTING Heatstroke treatment unit, Makkah, Saudi Arabia. PATIENTS A total of 25 patients were admitted during the annual Hajj pilgrimage in 1994. Ten patients evaluated in the same treatment center with minor illnesses and without pyrexia served as controls. INTERVENTIONS Patients were cooled according to an established evaporation method. MEASUREMENTS AND MAIN RESULTS Standard critical care parameters including continuous rectal temperature. A rapid immunochemical assay for serum procalcitonin was utilized. The mean serum procalcitonin was elevated 20-fold on admission in patients with heatstroke compared with controls (p < .011). The procalcitonin concentration subsequently increased to a plateau by 6 hrs and remained increased at 24 hrs, compared with the admission level (p < .0001). In this study, 77% of the patients with heatstroke survived. A subgroup analysis demonstrated that the patients who survived had a significantly higher procalcitonin concentration than those patients who died of heatstroke; a procalcitonin concentration of >0.5 ng/mL (>0.15 nmol/L) at 6 hrs predicted survival (p = .02). CONCLUSION Classic heatstroke is associated with increased concentrations of serum procalcitonin, particularly among survivors. Further studies are required to elucidate the source and action(s) of procalcitonin as well as its relationship to cytokine activation.

Procalcitonin and proinflammatory cytokine interactions in sepsis.

Immunoneutralization of procalcitonin (ProCT), a putative mediator of sepsis, has been shown to increase survival in an animal model of sepsis. To better understand the role that ProCT plays in the sepsis cascade, we studied the relationship of this hormone to the proximal proinflammatory mediators, IL-1beta and TNFalpha. Hamsters were made septic by i.p. implantation of Escherichia coli-impregnated agar pellets. A time line study of serum IL-beta, TNFalpha, and ProCT levels showed that the increase in the cytokines was transient and less than 2-fold over baseline, whereas ProCT increased >100-fold by 12 h and remains elevated through 24 h. TNFalpha (400 microg/kg) was injected into healthy animals, inducing an elevation in ProCT that was 25-fold greater than controls. ProCT (30 microg/kg) was given to healthy and septic animals. In healthy animals, there was no significant elevation in serum IL-1beta or TNFalpha levels. In septic animals, IL-1beta was modestly blunted at 3 h but not at 12 h, and there was no change in TNFalpha levels. ProCT did not initiate or enhance IL-1beta or TNFalpha expression; however, the massive and sustained elevation of this hormone seen in sepsis can be induced by the proximal cytokine, TNFalpha. This study suggests that ProCT is a secondary mediator that might augment and amplify but does not initiate the septic response. Immunoneutralization of ProCT may prove to be an important clinical strategy, in view of its sustained elevation and the difficulty in initiating therapy for sepsis during the early phases of illness.

Bacterial Complications of Respiratory Tract Viral Illness: A Comprehensive Evaluation

Abstract Background. Respiratory tract infection is one of the most common reasons for hospitalization among adults, and recent evidence suggests that many of these illnesses are associated with viruses. Although bacterial infection is known to complicate viral infections, the frequency and impact of mixed viral-bacterial infections has not been well studied. Methods. Adults hospitalized with respiratory illness during 3 winters underwent comprehensive viral and bacterial testing. This assessment was augmented by measuring the serum level of procalcitonin (PCT) as a marker of bacterial infection. Mixed viral-bacterial infection was defined as a positive viral test result plus a positive bacterial assay result or a serum PCT level of ≥ 0.25 ng/mL on admission or day 2 of hospitalization. Results. Of 842 hospitalizations (771 patients) evaluated, 348 (41%) had evidence of viral infection. A total of 212 hospitalizations (61%) involved patients with viral infection alone. Of the remaining 136 hospitalizations (39%) involving viral infection, results of bacterial tests were positive in 64 (18%), and PCT analysis identified bacterial infection in an additional 72 (21%). Subjects hospitalized with mixed viral-bacterial infections were older and more commonly received a diagnosis of pneumonia. Over 90% of hospitalizations in both groups involved subjects who received antibiotics. Notably, 4 of 10 deaths among subjects hospitalized with viral infection alone were secondary to complications of Clostridium difficile colitis. Conclusions. Bacterial coinfection is associated with approximately 40% of viral respiratory tract infections requiring hospitalization. Patients with positive results of viral tests should be carefully evaluated for concomitant bacterial infection. Early empirical antibiotic therapy for patients with an unstable condition is appropriate but is not without risk.