SEPSIS MANAGEMENT

Abstract

The present invention concerns methods for aiding in the risk assessment of a patient with suspected sepsis. For example, the risk of poor outcome (such as of a complicated clinical course and/or of mortality) can be assessed. The methods of the present invention may comprise the steps of (a) determining the amount of the biomarker Presepsin in a sample from a patient with suspected sepsis who has a known qSOFA (quick Sequential Organ Failure-Assessment) score of 0, 1, 2 or 3, (b) determining the amount of the biomarker Pro-calcitonin (PCT) in a sample from the patient, comparing the amounts determined in steps (b) and (c) to reference amounts, and (d) aiding in the risk assessment of a patient with suspected sepsis. The methods of the present invention may be computer-implemented.

Claims

1. A method for aiding in the risk assessment of a patient with suspected sepsis, comprising (a) determining the amount of the biomarker Presepsin in a sample from a patient with suspected sepsis who has a known qSOFA (quick Sequential Organ Failure-Assessment) score of 0, 1, 2 or 3, (b) determining the amount of the biomarker Procalcitonin (PCT) in a sample from the patient, (c) comparing the amounts determined in steps (b) and (c) to reference amounts, and (d) aiding in the risk assessment of a patient with suspected sepsis.

2. The method of claim 1, wherein the patient is a human patient.

3. The method of claim 1, wherein the sample is a blood, serum or plasma sample.

4. The method of claim 1, wherein the patient is a patient who presents with suspected sepsis.

5. The method of claim 1, wherein the risk of mortality, such as in-hospital mortality, a complicated clinical course, severe sepsis and/or septic shock is assessed.

6. The method of claim 5, wherein the complicated clinical course is defined as the need for organ support measures required during intensive care unit (ICU) stay, such as administration of intravenous fluids, vasopressors, mechanical ventilation or renal replacement therapy.

7. The method of claim 1, wherein the subject has a known qSOFA (quick Sequential Organ Failure-Assessment) score of 0 or 1.

8. The method of claim 7, wherein an amount of Presepsin in the sample from the subject which is larger than the reference amount for Presepsin and/or an amount of PCT in the sample from the subject which is larger than the reference amount for PCT is indicative for a subject who is at risk.

9. The method of claim 7, wherein an amount of Presepsin in the sample from the subject which is lower than the reference amount for Presepsin and an amount of PCT in the sample from the subject which is lower than the reference amount for PCT is indicative for a subject who is not at risk.

10. The method of claim 1, wherein the subject has a known qSOFA (quick Sequential Organ Failure-Assessment) score of 2 or 3.

11. The method of claim 10, wherein an amount of Presepsin in the sample from the subject which is larger than the reference amount for Presepsin and/or an amount of PCT in the sample from the subject which is larger than the reference amount for PCT is indicative for a subject who is at risk.

12. The method of claim 10, wherein an amount of Presepsin in the sample from the subject which is lower than the reference amount for Presepsin and an amount of PCT in the sample from the subject which is lower than the reference amount for PCT is indicative for a subject who is not at risk.

13. The method of claim 1, further comprising recommending or initiating a suitable therapeutic measure.

14. The method of claim 13, wherein the therapeutic measure is selected from recommended guidelines for management of sepsis, if the subject has been assessed to be at risk.

15. The method of claim 13, wherein the therapeutic measure may be treatment of infection or further investigation or other aspects of care deemed necessary by a practitioner, if the subject has been assessed to be not at risk.

16. The method of claim 1, wherein the reference amount for Presepsin is within a range from about 500 pg/mL to about 1500 pg/mL or about 750 pg/mL to about 1250 pg/mL, and/or wherein the reference amount for PCT is within a range from about 1.5 ng/mL to about 2.5 ng/mL.

17. A method for aiding in the risk assessment of a patient with suspected sepsis, comprising (a) obtaining the patient's qSOFA (quick Sequential Organ Failure-Assessment) score, (b) determining the amount of the biomarker Presepsin in a sample from the patient with suspected sepsis, (c) determining the amount of the biomarker Procalcitonin (PCT) in a sample from the patient, (d) comparing the amounts determined in steps (b) and (c) to reference amounts, and (e) aiding in the risk assessment of the patient.

18. The method of claim 17, wherein the patient's qSOFA score is based on the patient's respiratory rate (>22/min), the patient's systolic blood pressure (<100 mmHg), and the presence or absence of an altered mentation (GCS <15).

19. A computer-implemented method for the assessment of a patient with suspected sepsis, comprising (a) receiving at a processing unit (a1) a value for the amount of the biomarker Presepsin in a sample from a patient with suspected sepsis who has a known qSOFA (quick Sequential Organ Failure-Assessment) score of 0, 1, 2 or 3 and (a2) a value for the amount of the biomarker Procalcitonin in a sample from the patient, (b) processing the values received in step (a) with the processing unit, wherein said processing comprises (b1) retrieving from a memory one or more threshold values for the amount of the biomarker Presepsin, and one or more threshold values for the amount of the biomarker Procalcitonin, (b2) comparing the values received in step (a) with the respective threshold values retrieved in step (b1), and (c) providing an assessment of the patient via an output device, wherein said assessment is based on the results of step b).

20. A computer-implemented method for the assessment of a patient with suspected sepsis, comprising (a) receiving at a processing unit (a1) a value for the patient's qSOFA (quick Sequential Organ Failure-Assessment) score, (a2) a value for the amount of the biomarker Presepsin in a sample from the patient, and (a3) a value for the amount of the biomarker Procalcitonin in a sample from the patient, (b) processing the values received in step (a) with the processing unit, wherein said processing comprises (b1) retrieving from a memory a threshold value for the qSOFA score, one or more threshold values for the amount of the biomarker Presepsin, and one or more threshold values for the amount of the biomarker Procalcitonin, (b2) comparing the values received in step (a) with the respective threshold values retrieved in step (b1), and (c) providing an assessment of the patient via an output device, wherein said assessment is based on the results of step b).

21. The method of claim 19, wherein the output device is a display, configured for presenting the assessment.

22. The method of claim 21, wherein the value for the amount of the biomarker Presepsin and/or Procalcitonin is the value for the amount of the biomarker in a blood, serum or plasma sample.

Description

[0201] FIG. 1 Combined assessment of Presepsin (PSEP) and Procalcitonin (PCT) in addition to the qSOFA score improves the prediction of a complicated clinical course (severe sepsis, septic shock and mortality) in patients with early sepsis admitted to the emergency department

EXAMPLES

[0202] The invention will be merely illustrated by the following Examples. The said Examples shall, whatsoever, not be construed in a manner limiting the scope of the invention.

Example 1: Assessment of Presepsin (PSEP), Procalcitonin (PCT) and the Quick SOFA Score in Patients with Suspected Sepsis

[0203] Presepsin (soluble sCD14 subtype, sCD14-ST) is a circulating molecule fragment derived from sCD14 and serves as mediator of lipopolysaccharid (LPS) response against infectious agents. Presepsin has been shown to be beneficial as sepsis marker.

[0204] PCT is a member of the calcitonin (CT) superfamily of peptides. Due to PCT's variance between microbial infections and healthy individuals, it has become a marker to improve identification of systemic bacterial infection. Measurement of Procalcitonin can be used as a marker of severe sepsis caused by bacteria and correlates with the degree of sepsis.

[0205] The Sequential Organ Failure Assessment (SOFA) score was documented as well as respiratory rate, systolic blood pressure (RRsyst) and altered mentation (GCS score) enabling the calculation of the Quick SOFA (qSOFA) score retrospectively.

[0206] In 99 patients with suspected sepsis admitted to the emergency department (ED) Presepsin (PSEP), Procalcitonin (PCT) and the SOFA score were determined upon admission. Additional measured parameters were CRP, creatinine and lactate. The Sequential Organ Failure Assessment (SOFA) score was documented as well as respiratory rate, systolic blood pressure (RRsyst) and altered mentation (GCS score) to calculate the Quick SOFA (qSOFA) score retrospectively. Primary endpoint was death within 30 days. The combined endpoint “major adverse event” (MAE) consisted of at least one of the primary or the secondary endpoints (EP)—need of intensive care (ITS), mechanical ventilation or dialysis. EDTA plasma samples were collected at first presentation.

Example 2: Results

[0207] Median values of PSEP and PCT were 688 (IQR: 391-1143) pg/mL, and 1.39 (IQR: 0.385-4.29) ng/mL in the group with uncomplicated sepsis (N=66) and 1266 (IQR: 746-2267) pg/mL, p=0.0003, and 2.73 (IQR: 0.90-16.5) ng/mL in patients with septic shock or with complicated clinical course, p=0.0242, respectively. The 30-day mortality was 18.1% (n=18) overall, but in the group with septic shock 36.6% (n=15). The discrimination between survivors (n=81) and non-survivors (n=18) by ROC analysis revealed AUC values of 0.772, 0.519 and 0.802 of PSEP, PCT and qSOFA, respectively. The combination of PSEP, PCT and qSOFA by logistic regression revealed an AUC value of 0.850. [0208] 24 patients were assigned to qSOFA=0, 44 patients to qSOFA=1, 23 patients to qSOFA=2, and 8 patients to qSOFA=3. [0209] In 62.5% of the patients with qSOFA=0 the certainty with which a complicated clinical course (CCC) is ruled-out could be improved by using additionally the algorithm PSEP <1000 pg/mL and PCT <2 ng/mL (Tab1.1). [0210] In patients with qSOFA=1 the algorithm could differentiate between low risk and high risk of a complicated clinical course in 34.0% and 65.9%, respectively (Tab1.2). [0211] In patients with qSOFA=2 the algorithm could indicate the majority of 73.9% to rule in a complicated clinical course and 26% to rule out (Tab1.3). [0212] In patients with qSOFA=3 the algorithm could indicate 87.5% to rule in a complicated clinical course and 12.5% to rule out (Tab1.4).

[0213] Summary of ED Study Results:

TABLE-US-00001 Rule-out: Rule-in: PSEP < PSEP ≥ 1000 1000 pg/mL and pg/mL and/ Non- No PCT < or PCT ≥ Survi- survi- CCC CCC 2 ng/mL) 2 ng/mL vors vors All 33 66 81 18 n = 99 qSOFA = 0 11 13 15 9 24 0 n = 24 (62.5%) (37.5%) qSOFA = 1 29 15 17 27 39 5 n = 44 (34.0%) (65.9%) qSOFA = 2 19 4  6 17 17 7 n = 23 .sup. (26%) (73.9%) qSOFA = 3 7 1  1 7 2 6 n = 8 (12.5%) (87.5%)

[0214] Calculation of the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of qSOFA, qSOFA+PCT and qSOFA+PCT+PSEP in predicting hospital mortality and septic shock: [0215] 1. Discrimination of death vs alive by receiver operating characteristics curve (ROC) analysis

TABLE-US-00002 Sensi- Speci- NPV PPV AUC tivity % ficity % % % qSOFA + PCT + PSEP 0.852 89.4 7 64.13 96.7 34.0 qSOFA + PSEP 0.848 78.95 73.91 94.4 39.0 qSOFA + PCT 0.824 84.21 72.83 95.7 39.0 qSOFA 0.801 68.42 77.17 92.2 38.2 [0216] 2. Discrimination of septic shock vs uncomplicated sepsis by receiver operating characteristic curve (ROC) analysis

TABLE-US-00003 Sensi- Speci- NPV PPV AUC tivity % ficity % % % qSOFA + PCT + PSEP 0.817 73.81 76.81 82.8 66.0 qSOFA + PSEP 0.810 78.57 76.81 85.5 67.3 qSOFA + PCT 0.794 54.76 92.75 77.1 82.1 qSOFA 0.765 53.66 84.72 76.2 66.7 [0217] Sensitivity: Probability that a test result will be positive when the disease is present (true positive rate). [0218] Specificity: Probability that a test result will be negative when the disease is not present (true negative rate). [0219] Positive predictive value (PPV): Probability that the disease is present when the test is positive. [0220] Negative predictive value (NPV): Probability that the disease is not present when the test is negative.

Example 2: Individual Case Studies

[0221] Patients with qSOFA=0

[0222] Study ID 402

[0223] A 71 years old men (size 182 cm, weight 83 Kg, BMI 25) was admitted to the emergency department with fever and unclear genesis. The measured temperature was 39.7° C.

[0224] Respiratory rate, RRsyst and the GSC score were 24/min, 101 mmHg and 15, respectively, revealing a qSOFA score of 0.

[0225] PSEP and PCT were 693 pg/mL and 1.1 ng/mL indicating rule out of complicated clinical cause according to the algorithm.

[0226] The patient was admitted to the general ward and could be discharged after 12 days at home without complications.

[0227] Study ID 387

[0228] A 76 years old women was admitted to the emergency department with pneumonia (size 158 cm, weight 53 Kg, BMI 21.3). Respiratory rate, RRsyst and the GSC score were 26/min, 123 mmHg and 15, respectively, revealing a qSOFA score of 0.

[0229] PSEP and PCT were 287 pg/mL and 0.1 ng/mL indicating rule out of complicated clinical cause according to the algorithm.

[0230] The patient could be discharged at home from the emergency department.

[0231] Patients with qSOFA=1

[0232] Study ID 383

[0233] A 73 years old men (size 168 cm, weight 88 Kg, BMI=31) was admitted to the emergency department with pneumonia. Respiratory rate, RRsyst and the GSC score were 28/min, 125 mmHg and 15, respectively, revealing a qSOFA score of 1.

[0234] PESP and PCT were 3744 pg/mL and 0.56 ng/mL indicating moderate risk for prediction of complicated clinical cause and mortality risk according to the algorithm “qSOFA=1, PSEP >1000 pg/mL or PCT <2 ng/mL” indicates The PSEP concentration was >1000 pg/mL but the measured PCT value of 0.56 ng/mL was below the threshold of 2 ng/mL.

[0235] According qSOFA=1 and the very high PSEP value of 3744 pg/mL the patient was assigned to complicated clinical cause and admitted to the ICU. Instead of mechanical ventilation and dialysis the patient died after 25 days during the ICU stay.

[0236] Study ID 360

[0237] A 84 years old patient (size 162 cm, weight 60 Kg, BMI=22.9) was admitted to the emergency department with urinary tract infection. Respiratory rate, RRsyst and the GSC score were 22/min, 112 mmHg and 15, respectively, revealing a qSOFA score of 1.

[0238] PSEP and PCT values were 1517 pg/mL and 0.54 ng/mL indicating moderate risk of complicated clinical cause.

[0239] The patient was admitted to the general ward for antibiotic therapy and could be discharged after 7 days at home.

[0240] Study ID 313

[0241] A 42 years old men was admitted to the emergency department with pneumonia (size 178 cm, weight 101 Kg, BMI 31.9). Respiratory rate, RRsyst and the GSC score were 22/min, 130 mmHg and 15, respectively, revealing a qSOFA score of 1.

[0242] PSEP and PCT were 799 pg/mL and 0.26 ng/mL indicating low risk of complicated clinical cause according to the algorithm.

[0243] The patient was admitted to the general ward and received antibiotic therapy for 14 days until he was discharged at home without complications.

[0244] Study ID 458

[0245] A 87 years old men was admitted to the emergency department with urosepsis (size 160 cm, weight 70 Kg, BMI 27.3). Respiratory rate, RRsyst and the GSC score were 20/min, 147 mmHg and 11, respectively, revealing a qSOFA score of 1.

[0246] PSEP and PCT were 342 pg/mL and 6.4 ng/mL indicating high risk of complicated clinical cause according to the elevated PCT concentration. Also clinically the patient was assigned to severe sepsis underlined by a high CRP concentration of 102 mg/L.

[0247] The patient was admitted to the intensive care unit for two days and received early goal directed therapy. After further treatment at the general ward for 9 days the patient could be discharged at home without complications.

[0248] Study ID 461

[0249] A 68 years old women was admitted to the emergency department with pneumonia (size 174 cm, weight 103 Kg, BMI 34.2). Respiratory rate, RRsyst and the GSC score were 20/min, 110 mmHg and 14, respectively, revealing a qSOFA score of 1.

[0250] PSEP and PCT were 236 pg/mL and 8.1 ng/mL indicating high risk of complicated clinical cause according to the elevated PCT concentration. Also clinically the patient was assigned to severe sepsis underlined by a high CRP concentration of 102 mg/L.

[0251] The patient was admitted to the intensive care unit for three days and received early goal directed therapy. After further treatment at the general ward 7 the patient could be discharged at home without complication.

[0252] Patients with qSOFA=2

[0253] Study ID 403

[0254] A 87 years old men was admitted to the emergency department with urosepsis (size 175 cm, weight 65 Kg, BMI 21.2). Respiratory rate, RRsyst and the GSC score were 24/min, 74 mmHg and 15, respectively, revealing a qSOFA score of 2.

[0255] The algorithm “qSOFA=2, PSEP >1000 pg/mL or PCT >2 ng/mL” indicates prediction of complicated clinical cause and high mortality risk. The patient was admitted to the ICU for early goal directed therapy according to PSEP and PCT concentration of 1979 pg/mL and 16 ng/mL, respectively, measured at presentation.

[0256] After discharge from the ICU to the general ward the antibiotic therapy was continued but the patient died 5 days later.

[0257] Study ID 390

[0258] A 64 years female with abdominal pain due to acute cholecystitis was admitted to the emergency department (size 163 cm, weight 106 Kg, BMI 40). The qSOFA score at presentation was 2 (Respiratory rate, RRsyst and the GSC score were 28/min, 108 mmHg and 3).

[0259] PSEP and PCT values were 1858 pg/mL and 292 ng/mL indicating underlying sepsis with complicated clinical cause.

[0260] The patient was admitted to the ICU for early goal directed therapy and needed mechanical ventilation. After 5 days on the ICU and 10 days on the general ward the patient could be discharged at home.

[0261] Study ID 357

[0262] A 79 years old female (size 160 cm, weight 70 Kg, BMI 27) was admitted to the emergency department with urosepsis. Respiratory rate, RRsyst and the GSC score were 25 min, 140 mmHg and 13, respectively, revealing a qSOFA score of 2.

[0263] PESP and PCT were 1810 ng/L and 2.15 μg/L indicating high risk for prediction of complicated clinical cause and mortality risk according to the algorithm “qSOFA=1, PSEP >1000 pg/mL, PCT >2 ng/mL”.

[0264] The patient received early goal directed therapy and antibiotic therapy for 18 days at the general ward until discharge at home.

[0265] Patients qSOFA=3

[0266] Study ID 374

[0267] A 87 years old men (size 170 cm, weight 65 Kg, BMI 22.5) suffered from urinary tract infection and was admitted to the emergency department. Respiratory rate, RRsyst and the GSC score were 24/min, 80 mmHg and 3, respectively, revealing a qSOFA score of 3.

[0268] The algorithm “qSOFA=3, PSEP >1000 pg/mL or PCT >2 ng/mL” indicated prediction of complicated clinical cause and high mortality risk. The PSEP concentration of 8238 pg/mL was extremely high whereas and the PCT value was below 2 ng/mL (0.91 μg/L). Although PCT was <2 ng/mL high risk of worse outcome and mortality risk of >50% could be expected.

[0269] The high PSEP concentration of 8238 pg/mL might also be influenced through acute kidney disease (AKD) which was indicated by a measured creatinine concentration of 1022 μmon. AKD occurs commonly in sepsis and contributes to mortality risk significantly.

[0270] The patient was admitted to the intensive care unit for early goal directed therapy and died after 5 days.

[0271] Study ID 373

[0272] A 82 years old men with pneumonia was admitted to the emergency department. Respiratory rate, RRsyst and the GSC score were 24/min, 100 mmHg and 7, respectively, revealing a qSOFA score of 3.

[0273] The algorithm “qSOFA=3, PSEP >1000 pg/mL or PCT >2 ng/mL” indicates prediction of complicated clinical cause and high mortality risk. The PSEP concentration was >1000 pg/mL (1407 ng/L) but the measured PCT value of 0.37 ng/mL was below the threshold of 2 ng/mL of the algorithm and below 0.5 ng/mL.

[0274] According qSOFA=3 and PSEP >1000 pg/mL the patient was assigned to complicated clinical cause and admitted to the ICU. Despite intensive care with mechanical ventilation and dialysis during the ICU stay the patient died after 7 days.

[0275] Study ID 381

[0276] A 78 years old female was admitted to the emergency department urinary tract infection. Respiratory rate, RRsyst and the GSC score were 30/min, 91 mmHg and 12 revealing a qSOFA score of 3.

[0277] The PSEP concentration of 504 pg/mL was below the threshold of 1000 pg/mL whereas the PCT value was 2 pg/ml. According to the algorithm qSOFA=3, PSEP <1000 pg/mL but PCT ≥2 ng/mL complicated clinical causes like severe sepsis or septic shock could not be excluded. The patient was admitted to the general ward for antibiotic treatment and was discharged after 9 days without complications.

[0278] Study ID 389

[0279] A 75 years old men was admitted to the emergency department with urosepsis (size 165 cm, weight 100 Kg, BMI 36.7). Respiratory rate, RRsyst and the GSC score were 24/min, 100 mmHg and 11, respectively, revealing a qSOFA score of 3.

[0280] The PSEP concentration of 3496 pg/mL was above the threshold of 1000 pg/mL and the PCT value was 25.6 ng/mL. According to the algorithm qSOFA=3, PSEP >1000 pg/mL and PCT ≥2 ng/mL complicated clinical causes like severe sepsis or septic shock could not be excluded.

[0281] The patient was admitted to the ICU for 4 days because of need of dialysis due to acute kidney disease. After discharge to the general ward the patient died after 9 days during hospital stay.

CONCLUSIONS

[0282] In patients with qSOFA=0 or qSOFA=1 and a PCT concentration of <2 ng/mL and Presepsin concentration of <1000 pg/mL, a clinical course without risk of complications may be assumed for the patient. If one of the two biomarkers exceeds the respective limit value, a clinical course without risk of complications cannot be safely eliminated. In a study of 99 patients with suspected sepsis in the emergency room, for 24 patients with qSOFA=0 and for 44 patients with qSOFA=1, a complicated clinical course only could be excluded in 62.5% and 65.9% of cases respectively, although these patients exhibited a “negative” qSOFA (<2)

[0283] In patients with qSOFA=2 and a PCT concentration of <2 ng/mL and a Presepsin concentration of <1000 pg/mL, a good prognostic course can be expected, despite the “positive” qSOFA score. In the above study 26% of patients with qSOFA=2 had an uncomplicated clinical course. On the other hand, patients with a PCT concentration of >2 ng/mL and/or a Presepsin concentration of >1000 pg/mL are at an increased risk of a complicated clinical course. Patients like this must be monitored by medical staff, if necessary in the intensive care unit. In the same emergency study in 23 patients with qSOFA=2, a complicated clinical course was reliably predicted in 73% of cases.

[0284] In patients with qSOFA=3 and a PCT concentration and Presepsin concentration of over 2 ng/mL and ≥1000 pg/mL respectively, severe bacterial sepsis or septic shock is ensured with high mortality.

[0285] Thus, the findings of the present invention show that the combination of qSOFA with Presepsin and Procalcitonin is more accurate in predicting a complicated clinical course of sepsis and hospital mortality than the qSOFA score alone. Accordingly, the combined assessment of qSOFA, Presepsin and Procalcitonin according to the proposed algorithm improves the risk stratification of patients with suspected sepsis admitted to the emergency department significantly.