Can serum procalcitonin levels help interpret indeterminate chest radiographs in patients hospitalized with acute respiratory illness?

BACKGROUND: Clinical diagnosis of pneumonia is difficult and chest radiographs often indeterminate, leading to incorrect diagnoses and antibiotic overuse. OBJECTIVE: To determine if serum procalcitonin (ProCT) could assist in managing patients with respiratory illness and indeterminate radiographs. DESIGN: Subjects were prospectively enrolled during 2 consecutive winters. SETTING: A 520-bed hospital in Rochester, NY. PATIENTS: Five hundred twenty-eight adults admitted with acute respiratory illness were enrolled. MEASUREMENTS: Serum ProCT, admission diagnoses, and chest radiographic findings were used to derive receiver operating characteristics curves to assess predictive accuracy of ProCT for the presence of infiltrates. RESULTS: Subjects with pneumonia had higher ProCT (median 0.27 ng/ml) than those with exacerbations of chronic obstructive pulmonary disease (0.08 ng/ml), acute bronchitis (0.09 ng/ml), or asthma (0.06 ng/ml). ProCT had moderate accuracy for the presence of infiltrates (area under curve [AUC] 0.72), when indeterminate radiographs were independently classified as infiltrates by a pulmonologist evaluating patients. CONCLUSIONS: ProCT may be useful in diagnosing pneumonia when chest radiographs are indeterminate.

Utility of serum procalcitonin values in patients with acute exacerbations of chronic obstructive pulmonary disease: a cautionary note.

BACKGROUND: Serum procalcitonin levels have been used as a biomarker of invasive bacterial infection and recently have been advocated to guide antibiotic therapy in patients with chronic obstructive pulmonary disease (COPD). However, rigorous studies correlating procalcitonin levels with microbiologic data are lacking. Acute exacerbations of COPD (AECOPD) have been linked to viral and bacterial infection as well as noninfectious causes. Therefore, we evaluated procalcitonin as a predictor of viral versus bacterial infection in patients hospitalized with AECOPD with and without evidence of pneumonia. METHODS: Adults hospitalized during the winter with symptoms consistent with AECOPD underwent extensive testing for viral, bacterial, and atypical pathogens. Serum procalcitonin levels were measured on day 1 (admission), day 2, and at one month. Clinical and laboratory features of subjects with viral and bacterial diagnoses were compared. RESULTS: In total, 224 subjects with COPD were admitted for 240 respiratory illnesses. Of these, 56 had pneumonia and 184 had AECOPD alone. A microbiologic diagnosis was made in 76 (56%) of 134 illnesses with reliable bacteriology (26 viral infection, 29 bacterial infection, and 21 mixed viral bacterial infection). Mean procalcitonin levels were significantly higher in patients with pneumonia compared with AECOPD. However, discrimination between viral and bacterial infection using a 0.25 ng/mL threshold for bacterial infection in patients with AECOPD was poor. CONCLUSION: Procalcitonin is useful in COPD patients for alerting clinicians to invasive bacterial infections such as pneumonia but it does not distinguish bacterial from viral and noninfectious causes of AECOPD.

Exogenous procalcitonin evokes a pro-inflammatory cytokine response.

OBJECTIVE AND DESIGN: Procalcitonin (ProCT) is increased in serum of septic patients and those with systemic inflammation. Endogenous levels of ProCT might influence the response of polymorphonuclear leukocytes (PMNs), independently of endotoxin, in clinical disease. SUBJECTS: Healthy human volunteers. TREATMENT: Recombinant human ProCT (rhProCT). METHODS: Whole blood and PMNs were exposed in vitro to exogenous rhProCT. Interleukin (IL)-6, IL-8, IL-10, IL-13, tumor necrosis factor-alpha (TNFα), IL-1ß, and macrophage inflammatory protein (MIP)-1ß (pg/ml) were measured by multiplex suspension bead-array immunoassay, and migration and phagocytosis were measured in PMNs. RESULTS: In a whole-blood model, a dose-dependent increase in IL-6, TNFα, and IL-1ß of the cell-free supernatant was noted. Pre-incubation with ProCT, at doses consistent with clinical sepsis, resulted in a decrease in PMN migration without alteration in phagocytosis of Staphylococcus aureus or indirect measurements of bacterial killing. CONCLUSION: Clinically relevant levels of ProCT influence immunologic responses that may contribute to systemic inflammatory response and septic shock.

Gut barrier dysfunction in critically ill surgical patients with abdominal compartment syndrome.

OBJECTIVES: This study investigated the effects of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) on gut barrier function in critically ill surgical patients. METHODS: A prospective observational cohort study on patients with severe acute pancreatitis or abdominal sepsis admitted to an intensive care or high-dependency unit. Intra-abdominal pressure (IAP) and plasma levels of immunoglobulin G (IgG) and IgM antiendotoxin core antibodies (EndoCAb) and procalcitonin (ProCT) were measured serially. RESULTS: Among 32 recruited patients, 24 (75%) and 8 patients (25%) developed IAH and ACS, respectively. The state of ACS was associated with significant reductions in plasma IgG EndoCAb (P = 0.015) and IgM EndoCAb (P = 0.016) and higher concentrations of plasma ProCT (P = 0.056) compared with absence of ACS. Resolution of IAH and ACS was associated with significant recovery of plasma IgG EndoCAb (P = 0.003 and P = 0.009, respectively) and IgM EndoCAb (P = 0.002 and P = 0.003, respectively) and reduction in plasma ProCT concentration (P = 0.049 and P = 0.019, respectively). Negative correlations were observed between IAP and plasma IgG EndoCAb (P = 0.003) and IgM EndoCAb (P = 0.002). CONCLUSIONS: Intra-abdominal hypertension and ACS are associated with significantly higher endotoxin exposure and ProCT concentrations, suggestive of gut barrier dysfunction. Resolution of IAH and ACS is associated with evidence for recovery of gut barrier function.

Procalcitonin has bioactivity at calcitonin receptor family complexes: potential mediator implications in sepsis.

CONTEXT: Sepsis is a major cause of death in the United States and accounts for approximately 50% of the fatalities in intensive care units. Serum procalcitonin (ProCT) levels are markedly elevated in sepsis and correlate positively with severity of the illness and mortality, however, little is known about the biological activity of ProCT. OBJECTIVE: To explore the biological activity of purified human ProCT at the calcitonin (CT) family of receptors. DESIGN: Human ProCT was purified from the TT medullary thyroid carcinoma cell line. Human CTa receptor or human CT receptor-like receptor (CLR) was transiently expressed in COS-7 cells alone or together with individual receptor activity-modifying proteins (RAMPs) to generate the CTa (CT) receptor, the AMY1 (amylin) receptor, the CGRP1 (CT gene-related peptide) receptor, and the AM1 and AM2 (adrenomedullin) receptors. Biological activity of ProCT was assessed by measurement of cAMP accumulation. RESULTS: ProCT was effectively inert at CTa, AM1, and AM2 receptors. In contrast, it was a potent partial agonist (50-60% of the CGRP efficacy) of the CGRP1 receptor with an EC50 as high as 0.56 nM, although the potency was batch dependent. ProCT also displayed weak partial agonist activity at the AMY1 receptor with an EC50 of approximately 100 nM. Moreover, ProCT also robustly inhibited CGRP-dependent cyclic adenosine monophosphate responses at the CGRP1 receptor. CONCLUSIONS: Our data provide a potential molecular mechanism for the observation that ProCT appears to be toxic while CGRP treatment appears to be beneficial in animal models of sepsis.

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.

Early immunoneutralization of calcitonin precursors attenuates the adverse physiologic response to sepsis in pigs.

OBJECTIVE: The 116 amino acid prohormone procalcitonin and some of its component peptides (collectively termed calcitonin precursors) are important markers and mediators of sepsis. In this study, we sought to evaluate the effect of immunoneutralization of calcitonin precursors on metabolic and physiologic variables of sepsis in a porcine model. DESIGN: A prospective, controlled animal study. SETTING: A university research laboratory. SUBJECTS: 30-kg Yorkshire pigs. INTERVENTIONS: Sepsis was induced in 15 pigs by intraperitoneal instillation of a suspension of cecal content (1 g/kg animal body weight) and a toxinogenic Escherichia coli solution (2 x 10(11) colony-forming units). During induction of sepsis, seven pigs received an intravenous infusion of purified rabbit antiserum, reactive to the aminoterminal portion of porcine prohormone procalcitonin. Another eight control pigs received an intravenous infusion of purified nonreactive rabbit antiserum. For all 15 animals, physiologic data (urine output, core temperature, arterial pressure, heart rate, cardiac index, and stroke volume index) and metabolic data (serum blood urea nitrogen and creatinine, arterial lactate, and pH) were collected or recorded hourly until death at 15 hrs. MEASUREMENTS AND MAIN RESULTS: In this large-animal model of rapidly lethal peritonitis, serum calcitonin precursors were significantly elevated. Amino-prohormone procalcitonin-reactive antiserum administration resulted in a significant improvement or a beneficial trend in a majority of the measured physiologic and metabolic derangements induced by sepsis. Specifically, arterial pressure, cardiac index, stroke volume index, pH, and creatinine were all significantly improved, while urine output and serum lactate had beneficial trends. Treated animals also experienced a statistically significant increase of short-term survival. CONCLUSIONS: These data from a large-animal model with polymicrobial sepsis demonstrate the salutary effect of early immunoneutralization of calcitonin precursors on physiologic and metabolic variables. Immunologic blockade of calcitonin precursors may offer a novel therapeutic approach to human sepsis.

Pulmonary immunoreactive calcitonin in the African green monkey (Cercopithecus aethiops): Anatomic distribution.

The hormone calcitonin, which occurs predominantly within the C cells of the mammalian thyroid gland, is also found within the pulmonary endocrine cells of the epithelium of the tracheobronchial tree. A study was made of the distribution of immunoreactive calcitonin (iCT) in the African green monkey. Using two different region-specific antisera, the total respiratory iCT comprised 2.5% and 5.8% of the total thyroid iCT. The mean concentration of iCT in the right lung exceeded that in the left, and the mean concentration of the right middle or right upper lobe exceeded that of all other lobes. Embryologically, the ultimobranchial bodies contribute their iCT-producing C cell primordia to the thyroid gland near the level of the primitive laryngotracheal cleft and shortly after the early arborization of the bronchial tree. In monkeys and most other mammals, the right main stem bronchus is larger and develops earlier than the left. The data suggest an early migration of cells from the ultimobranchial bodies to the bronchi, eventually giving rise to the iCT-containing pulmonary endocrine cells.