PCT. PCT in Bacterial Infections and Sepsis. Early Diagnosis. Assessment of Severity and Prognosis. Support for Therapeutic Decision Making

Transcription

1 PCT PCT in Bacterial Infections and Sepsis Early Diagnosis Assessment of Severity and Prognosis Support for Therapeutic Decision Making

2 Diagnosis and monitoring of sepsis Clinical need for earlier detection of sepsis Early detection and specific clinical intervention has been shown to be crucial for the improved outcome of patients with sepsis. However, sepsis can be difficult to distinguish from other, non-infectious conditions in critically ill patients with clinical signs of acute inflammation. Therefore, in the early phase of the disease process it may be difficult to decide on the appropriate therapeutic measures for the individual patient. Additional specific information may be helpful to increase the accuracy of sepsis diagnosis at an early stage. A parameter which fulfils these demands to a high degree is procalcitonin (PCT) Clinical condition Healthy Local infections Systemic infections (sepsis) Severe sepsis Septic shock Figure : PCT increase reflects the continuous development from a healthy condition to the most severe states of disease (severe sepsis and septic shock). PCT fast and highly specific increase in bacterial infection and sepsis One major advantage of PCT compared to other parameters is its early and highly specific increase in response to severe systemic bacterial infections and sepsis.,5 Thus, in septic conditions increased PCT levels can be observed 3-6 hours after infectious challenge. PCT levels are usually low in viral infections, chronic inflammatory disorders or autoimmune processes. PCT levels in sepsis are generally greater than -2 ng/ml and often reach values between and ng/ml, or considerably higher in individual cases, thus enabling the diagnostic differentiation between these various clinical conditions and a severe bacterial infection (sepsis) (Figure ).

3 Early diagnosis confident decisions PCT best parameter for early sepsis diagnosis Among the available laboratory parameters PCT has been shown to be the most useful.,5,6,9 PCT has been demonstrated to be the best marker for differentiating patients with sepsis from those with systemic inflammatory reaction not related to infectious cause (Figure 2a, b). Figure 2: Comparison of diagnostic performances of various markers for diagnosis of bacterial infection/ sepsis Figure 2a: PCT versus CRP 6 PCT: Better differentiation of bacterial infection from noninfectious causes of inflammation Summary receiver operating characteristic (SROC) curves comparing serum procalcitonin (PCT; ) and C-reactive protein (CRP; ) markers for detection of bacterial infections versus non-infective causes of inflammation. Each point contributing to the SROC curve represents study (total number of studies: ; total number of patients: 95). Sensitivity % PCT pooled sensitivity: 88% pooled specificity: 75% CRP pooled sensitivity: 8% pooled specificity: 67% Specificity % Figure 2b: PCT versus IL-6 and IL-8 PCT: More accurate diagnosis of sepsis than IL-6 and IL-8 Receiver operating characteristics (ROC) curves comparing serum procalcitonin (PCT), interleukin 6 (IL-6) and interleukin 8 (IL-8) for detection of sepsis on day of admission to ICU. Sensitivity PCT AUC:.92 IL-6 AUC:.75 IL-8 AUC: specificity Only PCT improves accuracy of clinical sepsis diagnosis Moreover, PCT was shown to be the only laboratory parameter that made a significant contribution to the clinical diagnosis of sepsis (Figure 3). Information obtained from IL-6, IL-8 and CRP had no impact on the clinical diagnosis of sepsis on admission. Figure 3: Accuracy of sepsis diagnosis based on a clinical model with and without PCT Sensitivity Clinical model with PCT AUC:.94 Clinical model without PCT AUC: specificity

4 Early diagnosis confident decisions Increased PCT values best indicator for the severity of infection and organ dysfunction PCT development accurately reflects the progression of the disease more reliable than other parameters (Figure 4a-d). Figure 4a, b: Differentiation between SIRS*, sepsis, severe sepsis and septic shock by PCT and IL-6 * Systemic Inflammatory Response Syndrome. IL-6 [pg/ml]. SIRS Sepsis Severe sepsis Septic shock SIRS Sepsis Severe sepsis Septic shock Figure 4c, d: Assessment of severity of disease (increasing organ dysfunction) by PCT and CRP 3 p <. p <. p <.5 CRP [mg/l] p <.. n = 32 n = 6 n = 6 n = n = 32 n = 6 n = 6 n = Categories in the SOFA score Categories in the SOFA score PCT kinetics can be used to assess the effectiveness of treatment As the septic infection resolves, PCT reliably returns to values below.5 ng/ml, with a half-life of 24 hours. 3 Consequently, in vitro determinations of PCT can be used to monitor the course and prognosis of life-threatening systemic bacterial infections and to tailor the therapeutic interventions more efficiently (Figure 5). 8 E.g., this has been demonstrated for the monitoring of patients with ventilator-associated pneumonia (VAP) Immediate effectiveness of AB Secondary response to therapy with the change of AB Therapeutic failure 4 Figure 5: Typical course of PCT serum level according to patient s response to antibiotic treatment (n=9) Days

5 Impact on therapeutic decisions and cost reduction Initial studies on the economic implication of utilizing PCT in the diagnostic process did show that systematic use of PCT for sepsis diagnosis and monitoring may also have a positive impact on the reduction of antibiotic treatment, therefore allowing a shorter stay in the ICU and lower costs per case (Figure 6). 6,2,8 Duration of AB treatment in hospital (days) A (without PCT) B (with PCT) Figure 6: Cost savings by reduction of AB treatment days PCT management of antibiotic use during an epidemic of enteroviral meningitis: Unnecessary antibiotic treatment was stopped after exclusion of the bacterial infection. The decision to stop antibiotic treatment at a PCT value of <.5 ng/ml, without clinical counter-argument (inappropriately pretreated bacterial meningitis excluded), resulted in saving 2.4 days of antibiotics per patient (29 j in 2 months). 2 References American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference, Crit Care Med 992, 2 (6): Brunkhorst FM et al. Int Care Med 2, 26(Suppl.2): Chiesa C et al. Clin Infect Dis 998, 26: Chiesa C et al. Clin Chem 23, 49(): Christ-Crain M et al. Lancet 24, 363(949): Christ-Crain M et al. Am J Respir Crit Care Med. 26, 74, Christ-Crain M & Müller B, Swiss Med Wkly 25, 35: Christ-Crain M et al. Chest 24, 26(4): 78s 9 Falcoz PE et al. Eur J Cardiovasc Surg 25, 27(6): Harbarth S et al. Am J Respir Crit Care Med 2, 64: Luyt CE et al. AJRCCM 25, 7: Marc E et al. Arch Pédiatr 22, 9: -7 3 Meisner M, Procalcitonin (PCT) - A new, innovative infection parameter. Biochemical and clinical aspects, ISBN: , Thieme Stuttgart, New York 2 4 Morgenthaler N et al. Clin Lab 22, 48(5-6): Müller B et al. Crit Care Med 2, 28(4): Simon L et al. CID 24, 39(2): Steinbach G et al. Clin Chem Lab Med 24, 42(4): Stüber F, 2 st Int. Congress of Intensive Care and Emergency Medicine (ISICEM), Brussels 2 9 Van Rossum AM et al. Lancet Infect Dis 24, 4(): 62-63

6 Diagnosis and monitoring of clinically relevant bacterial infections of the lower respiratory tract (LRTI) LRTI major cause of sepsis It is common knowledge that the majority of septic cases in the ICU are caused by LRTI, 5 LRTI should be considered as a potential pre-septic condition which requires early diagnosis and treatment. Such an approach may help to decrease the number of patients developing sepsis and, subsequently, increase their chance of survival. Early clinical assessment of LRTI by sensitive PCT measurement Sensitive PCT measurement techniques will capture minor elevations of PCT in the blood circulation 7,4,7 therefore the detection of clinically relevant bacterial infection is possible at a much earlier stage of the disease. Identification of LRTI patients who require antibiotic therapy It has been clinically proven that due to the high specificity of PCT for bacterial infection, PCT measurement at low concentrations can help to differentiate patients with clinically relevant LRTI who require antibiotic therapy (AB) from those with viral infection or minor bacterial infection who do not require antibiotic treatment. 5 Thus, for patients who are clinically assessed as requiring treatment with antibiotics, but who have low PCT values (<.25 ng/ml), it is recommended that antibiotics should not be administered. For patients with very low PCT values (<. ng/ml), AB treatment is strongly discouraged (see decision algorithm, Figure 7a). Using this PCT-based decision algorithm patients with infection of viral etiology or self-limiting disease are not unnecessarily exposed to antibiotics. Figure 7b: AB treatment based on standard clinical assessment of LRTI (standard group n=9) and guided by PCT level (PCT group n=24) 5 Patient groups with LRTI: CAP (Community-acquired pneumonia); AECOPD (Acute exacerbation of chronic obstructive pulmonary disease); Acute bronchitis; Acute exacerbation of asthma; Others Figure 7a: PCT cut-offs for the guidance of AB therapy in patients with suspicion for bacterial LRTI 5 Standard group PCT value on admission [ng/ml].5 >.25 - < <. Antibiotic therapy YES! Yes No NO! 6-2 h later re-assess clinically, re-measure PCT for confirmation of therapeutic decision Antibiotic prescriptions (%) Procalcitonin group 45/45 9/9 38/42 27/3 2/3 6/3 /29 4/28 2/5 / CAP AECOPD Bronchitis Asthma Others Thus, AB prescription potentially could be reduced to 5% of cases with LRTI, especially in patients with acute exacerbation of COPD and bronchitis, with similar clinical outcome for both groups (Figure 7b). 5,8

7 Early diagnosis confident decisions Tailoring the duration of antibiotic therapy to the individual need of the CAP patient Figure 8a: PCT-based decision algorithm (design of interventional study) 6 CAP (as defined according to international guidelines) A patient with community-acquired pneumonia (CAP) will usually be treated with AB for -4 days. It has now been demonstrated that the duration of therapy can be specifically guided for each patient by monitoring the development of PCT concentration over the course of antibiotic treatment. Thus, having decided on a PCT-based AB guided therapy, PCT values will be closely monitored. It is recommended that AB therapy conclude when PCT levels fall below.25 ng/ml and strongly recommended when PCT levels fall below. ng/ml (Figure 8a). 6 Standard group (without PCT) Randomization PCT group.5 >.25 - < <. AB treatment (prescription and duration according to evidence-based guidelines) AB therapy 6-2 h later YES! Yes No NO! Re-assess therapeutic decision by monitoring clinical course and PCT value AB duration (according to guidelines) Day 4, 6, 8 Decision on AB duration (STOP or continue) based on PCT cut-off and clinical course Follow-up after 4-6 weeks incl. Rx Medical and economic impact Therefore the integration of PCT into diagnostic and treatment algorithms allows both an earlier treatment and also more targeted use of clinical and financial resources by reducing expenditure on antibiotics reducing the number of treatment days. This PCT-based decision algorithm allows the tailoring of the duration of therapy to the individual clinical situation of each patient, so that total AB use will be strictly limited according to their specific clinical needs. Figure 8b: AB use at days -2 with and without PCT guidance (PCT group n=5, standard group n=5) 6 Patients on AB treatment (%) AB started Standard group PCT group >4d >6d >8d >d >4d >2d Consequently, with PCT guidance the duration of antibiotic therapy could be reduced from a median of 2 to 5 days (Figure 8b) with a similar outcome for both groups. 6

8 Early diagnosis confident decisions Interpretation of results Healthy individuals: Determination of normal values with a high sensitive assay revealed normal values to be below.5 ng/ml. 4 PCT serum concentrations are elevated in clinically relevant bacterial infections and continue to rise with the increasing severity of the disease. However, as an expression of individually different immune responses and different clinical situations, the same focus of infection may be associated with varying individual elevations in PCT concentrations. Therefore, clinicians should use the PCT results in conjunction with the patient s other laboratory findings and clinical signs, and interpret the concrete values in the context of the patient s clinical situation.* The reference ranges below are provided for orientational purpose only. Diagnosis of systemic bacterial infection/sepsis,,5 SIRS, sepsis, severe sepsis, and septic shock are categorized according to the criteria of the consensus conference of the American College of Chest Physicians/Society of Critical Care Medicine. PCT <.5 ng/ml Systemic infection (sepsis) is not likely. Local bacterial infection is possible. PCT.5 and < 2 ng/ml Systemic infection (sepsis) is possible, but various conditions are known to induce PCT as well.* PCT 2 and < ng/ml Systemic infection (sepsis) is likely, unless other causes are known.* PCT ng/ml Important systemic inflammatory response, almost exclusively due to severe bacterial sepsis or septic shock. Low risk for progression to severe systemic infection (severe sepsis). Caution: PCT levels below.5 ng/ml do not exclude an infection, because localized infections (without systemic signs) may be associated with such low levels. Also if the PCT measurement is done very early after a following bacterial challenge (usually < 6 hours), these values may still be low. In this case, PCT should be re-assessed 6-24 hours later. 5 Moderate risk for progression to severe systemic infection (severe sepsis). The patient should be closely monitored both clinically and by re-assessing PCT within 6-24 hours. High risk for progression to severe systemic infection (severe sepsis). High likelihood of severe sepsis or septic shock. Differential diagnosis of Lower Respiratory Tract Infections 5,8 PCT <. ng/ml PCT. and <.25 ng/ml PCT.25 and <.5 ng/ml PCT.5 ng/ml Indicates absence of bacterial infection. Use of antibiotics strongly discouraged, also in the presence of impaired pulmonary reserve in AECOPD. Bacterial infection unlikely. The use of antibiotics is discouraged. Bacterial infection is possible. Advice to initiate antimicrobial therapy. Suggests the presence of bacterial infection. Antibiotic treatment strongly recommended.

9 PCT reference ranges in neonates 3 Age in hours PCT values are physiologically increased during the first two days of life. Therefore a different reference range applies to premature and newborn infants (Table ). 3,4 The reference range for the first two days of life changes within a few hours (Figure 9a). However, also during the first 48 hours of life, the PCT values of newborns suffering from early sepsis are significantly higher than those of healthy newborns (Figure 9b). The adult reference range applies from three days after birth Table : Normal range in neonates (including 95% of all measurements) Time (h) Figure 9a: Healthy newborns 95% reference range of PCT in healthy newborns (n=83) in the first 48 hours after birth. Individual measurements are illustrated. The unbroken line characterizes the geometric mean and the dotted lines the 95% reference range Figure 9b: Septic newborns PCT values in neonates presenting symptoms of sepsis within the first 48 hours of birth. Individual measurements are displayed. The unbroken line refers to the geometric mean while the dotted lines refer to the 95% reference range in the non-infected normal population. 3 Time (h) * NOTE: Increased PCT levels may not always be related to systemic bacterial infection. There are a few situations described where PCT can be elevated by non-bacterial causes. These include, but are not limited to - neonates < 48 hours of life (physiological elevation) 3 (see reference values in Table and Figure 9) - the first days after a major trauma, major surgical intervention, severe burns, treatment with OKT3 antibodies and other drugs stimulating the release of pro-inflammatory cytokines 3 - patients with invasive fungal infections, acute attacks of plasmodium falciparum malaria 3 - patients with prolonged or severe cardiogenic shock, prolonged severe organ perfusion anomalies, small cell lung cancer, medullary C-cell carcinoma of the thyroid. 3 Low PCT levels do not automatically exclude the presence of bacterial infection. Such low levels may be obtained, e.g., during the early course of infections, in localized infections and in subacute endocarditis. Therefore, follow-up and re-evaluation of PCT in clinical suspicion of infection is pivotal. The PCT measuring technique should be chosen dependent on intended clinical use (see Figure ).

10 Practical aspects of PCT testing Frequently asked questions Answers PCT induction and kinetics What is PCT and where is it produced? PCT is the prohormone of calcitonin. Whereas CT is secreted by the C-cells of the thyroid after hormonal stimulation, PCT can be produced by numerous cell types and organs after proinflammatory stimulation, especially when caused by bacterial challenge. 7 Rapid increase after bacterial infection PCT increases ~3 hours after bacterial infection, reaching maximum values after 6-2 hours. 7,3 Half-life time in vivo About 24 hours Patient monitoring with PCT Frequency of PCT measurement for patient monitoring Interpretation of PCT concentrations during therapeutic monitoring*, e.g. after surgical removal of septic focus and/or after start of antibiotic therapy Minimum once per day ~5% reduction of PCT concentration per day over several days Indication for success of therapeutic intervention (surgery, antibiotic treatment) Persistent high or further increasing PCT levels Indication for non-controlled infectious process justifying a re-assessment of therapeutic strategy 6,7,,,3,8 Interpretation of PCT concentrations during infectious disease monitoring* of highrisk patients, e.g. after extended surgery or polytrauma Low PCT levels or significant reduction of primarily increased PCT levels (e.g. after extended surgery) during the following days by ~5% per day to reach low values after a couple of days No infectious complication Persistent increased PCT levels or newly increasing PCT levels indicate infectious complication Infectious complication 7,9,3 Sample material and stability Sample material for PCT measurement Human serum or plasma may be used. 3 * PCT values measured in patient samples of arterial blood are ~4% higher than in samples from venous blood. 3 Current assay formats are suitable for use with human serum or plasma only. Other human body fluids or samples from other species cannot be used. Stability In vitro stability Very stable in vitro, no special requirements for pre-analytical sample handling and storage 3 At room temperature ~2% decomposition rate during the first two hours after blood collection, ~% decomposition during the first 24 hours At -2 C Stable for months Freeze/thaw, 3 cycles < 2% loss of PCT in the sample * For patient monitoring the same sample matrix should always be used.

11 Protected by the following patents: USA N , N ; Europe N 656 2, N , N 88 72, N ; Germany N , N , N ; Japan N , N ; Australia N 686 4, China N ZL X, Russia N , South Africa N 93/642 Which assay to use? Today a rapid, semi-quantitative assay is available together with four different immunoassays for quantitative determination of PCT concentrations. All PCT determinations can be measured in either serum or plasma. Results available 9 minutes to 2.5 hours depending on the choice of method used. Choice of assay depends on intended clinical use (Figure ). (For detailed description of assays please see enclosed assay information.) Diagnosis PCT [ng/ml] Antibiotic use Assay RTI ICU Trauma Co-morb. COPD Septic shock Severe sepsis Sepsis Pneumonia Bronchitis COPD YES! Yes No NO! YES! Yes No NO! YES! Yes No B R A H M S PCT sensitive KRYPTOR B R A H M S PCT sensitive LIA B R A H M S PCT LIA LIAISON B R A H M S PCT Healthy NO!. Consider non-bacterial differential diagnosis Figure : Application of available PCT assays for various clinical settings (adapted from Christ-Crain & Müller 6 ) Cut-offs for clinical decision making (e.g. decision on prescription and duration of AB therapy) depend on the clinical setting. E.g., for patients with COPD and suspicion of infection antibiotics would be prescribed already at a lower PCT value compared to a trauma patient without concomitant disease. Decision to prescribe or withhold antibiotics should be re-assessed within the (second) 6-24 hours based on the patients clinical picture and PCT level. These values should also be considered in the clinical decision making process regarding the duration of antibiotic therapy as well as consideration of the clinical course of the disease.

12 B R A H M S products for intensive care and emergency medicine B R A H M S PCT-Q B R A H M S PCT sensitive KRYPTOR B R A H M S PCT sensitive LIA B R A H M S PCT LIA LIAISON B R A H M S PCT B R A H M S Neopterin-Screening EIA B R A H M S Neopterin EIA B R A H M S Neopterin RIA B R A H M S CRP ultrasensitive KRYPTOR * Please see the B R A H M S PCT LIA US package insert for details. Germany B R A H M S Aktiengesellschaft Neuendorfstr Hennigsdorf Phone: Fax: brahms@brahms.de Austria B R A H M S Diagnostica GmbH Schönbrunnerstr. 45/2/4 5 Wien Phone: Fax: office@brahms.at France B R A H M S France SAS 78-8, rue du Docteur Bauer 934 Saint Ouen Phone: Fax: brahms@brahms-france.fr Internet D 3422