Diagnosis and risk stratification of infections and chronic diseases of the respiratory tract and lungs by means of provasopressin, particularly copeptin or neurophysin II

Abstract

A method for diagnosing and/or stratifying the risk of infections or chronic diseases of the respiratory tract and lungs, particularly lower respiratory tract infections and chronic obstructive pulmonary disease, in which method provasopressin (proAVP) or fragments or partial peptides thereof, especially copeptin or neurophysin II, is/are determined. Suitable biomarker combinations for in-vitro diagnosis are also included.

Claims

1. A method for treating a patient having an infection or chronic disease of the airways and lungs and pneumonia, said method comprising: a determination of copeptin in at least one sample of body fluid from the patient, wherein the patient has a presence in said sample of bodily fluid of more than 40 pmol/L of copeptin which identifies the patient needing intensive therapy for pneumonia, and treating the patient with antibiotics.

2. The method according to claim 1, comprising a determination of copeptin in combination with procalcitonin and/or C-reactive protein (CRP) in the sample of bodily fluid of the patient.

3. The method according to claim 1, further comprising a determination of at least one inflammatory marker in the sample of bodily fluid of the patient.

4. The method according to claim 3, wherein the inflammatory marker is at least one of TNF-alpha, IL-6, VCAM or ICAM.

5. The method according to claim 3, wherein simultaneous determinations of the copeptin and inflammatory markers are carried out.

6. The method according to claim 5, wherein determinations are carried out using an automated analysis device.

7. The method according to claim 5, wherein determinations are carried out by means of a rapid test.

Description

EXAMPLES AND FIGURES

Example 1

(1) Blood samples were taken of patients who came to the emergency room of a hospital with the leading symptom of respiratory distress, during the initial examination.

(2) Number of test subjects: 167

(3) Sample-Taking, Biomarker Analysis:

(4) Blood samples were taken by means of standard serum Monovettes. After a coagulation period of 20-40 min, centrifugation was carried out for 15 min at 2000 g; subsequent serum separation was carried out by means of decanting. The serum samples were stored at 20 degrees C. until further use.

(5) Copeptin assay according to Morgenthaler et al (Morgenthaler N G, Struck J, Alonso C, et al. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin, Clin Chem 2006; 52:112-119).

(6) Detection limit: 1.7 pmol/L.

(7) COPD in the Case of Acute Worsening (Event):

(8) It was possible to determine that copeptin, CRP, and procalcitonin were significantly increased after 14 days or 6 months.

(9) Copeptin values of 167 patients (age (mean) 70 years) were studied. The patients came to the emergency room with acute exacerbation of an existing COPD. The patients were examined clinically with regard to their pulmonary function, at admission, after 14 days, and after 6 months. Table 1 shows an overview of the clinical parameters of the patients upon admission to the emergency room.

(10) TABLE-US-00001 TABLE 1 Clinical parameters at admission of 167 patients with acute exacerbation of a COPD Parameter n = 167 Sex (M/F) (%) 75/92 (44.9/55.1) Age in years (from to) 70 (42-91) Smoking packages/year 45 (30-60) {Translator's Note: The German word used, Packungen, translates literally to packages - unclear whether packs or cartons are meant} Average duration of COPD months (SD) 127 (86) Duration of exacerbation in days 4 (3-7) Cough (%) 142 (85) Increased sputum production (%) 113 (67.7) Discolored sputum (%) 95 (56.9) Difficulty breathing (%) 155 (92.8) Fever (%) 68 (40.7) Comorbidity (%) Cardiopathy 76 (45.5) Tumor 24 (14.4) Diabetes mellitus 19 (11.4) Severity of COPD - GOLD stage (%) I 10 (6.0) II 35 (21.0) III 74 (44.3) IV 48 (28.7) FEV1 in liters (SD) 0.892 (0.397) FEV1% expected (%) 39.9 (16.9) PaO.sub.2 mmHg 62.9 (15.7) PaCO.sub.2 mmHg 43.8 (11.0) Leukocytes 109/l (SD) 11.27 (4.7)

(11) In a multi-variant analysis (p=0.006, Cox Regression Analysis), the measured copeptin value was a predictor for a poor clinical progression, independent of age, existing comorbidity, hypoxemia, and restricted pulmonary function. It was only possible to achieve successful long-term therapy in 44 percent of the patients who had copeptin values 40 pmol/L upon admission. In contrast to this, it was possible to achieve success in 82 percent of the patients who had copeptin values <40 pmol/L (p<0.0001).

(12) From this, it becomes evident that copeptin represents a prognosis marker for a disadvantageous clinical progression in the case of patients with COPE (and other pulmonary diseases). Copeptin could identify those patients who need particularly intensive therapy for their existing pulmonary diseases, at an early point in time.

(13) Table 2 and FIGS. 2 and 3 explain the situation in detail.

(14) TABLE-US-00002 TABLE 2 Comparison of the clinical result of patients with copeptin levels <40 pmol/L and 40 pmol/L upon admission Copeptin <40 Copeptin 40 pmol/L pmol/L n = 140 n = 27 p value Hospitalization period 26.4% (37) 3.7% (1) 0.010 <24 hours % (n) Period of 8.5 (1-15) 14 (8-18) 0.002 hospitalization Days (IQR) Need for 6.4% (9) 25.9% (7) 0.002 intensive-care unit % (n) Period of 2 (1.5-4.5) 5 (3-5) 0.097 intensive-care unit (IQR) Hospitalization rate 0.17 0.4 0.55 0.74 0.005 within 6 months Average time to 163 45 111 73 <<0.001 clinical failure Long-term clinical 17.9% (25) 55.6% (15) <<0.001 failure % (n) Death during 1.4% (2) 11.1% (3) 0.007 hospitalization % (n) Death within 6 months 5% (7) 25.9% (7) <<0.001 % (n)

BRIEF DESCRIPTION OF THE DRAWINGS

(15) FIG. 1 shows the amino acid sequence (SEQ ID NO:3) of pre-provasopressin.

(16) FIG. 2 shows the relationship between stays in the hospital of patients with CAP/pneumonia and the measured copeptin plasma value upon admission. This is shown as a probability of hospital discharge over time. Patients with copeptin values <40 pmol/L upon admission had a significantly shorter hospital stay in comparison with patients with copeptin values > 40 pmol/L.

(17) Number of patients on the days indicated (d):

(18) Copeptin <40 pmol/L:

(19) n=140 (0 d) 88 (5 d) 54 (10 d) 28 (15 d) 12 (20 d) 1 (25 d) 1 (30 d) 0 (35 d)

(20) Copeptin 40 pmol/L:

(21) n=27 (0 d) 23 (5 d) 18 (10 d) 12 (15 d) 5 (20 d) 4 (25 d) 1 (30 d) 0 (35 d)

(22) FIG. 3 shows the relationship between the frequency of complications (death, repeat hospitalization after discharge) and the copeptin plasma value upon admission. This is shown as the time free of event (freedom of event). Event is defined as death or repeat hospitalization after initial discharge. Patients with copeptin values <40 pmol/L upon admission had this event significantly less frequently than patients with copeptin values >40 pmol/L. Number of patients on the days indicated (d):

(23) Copeptin <40 pmol/L:

(24) n=140 (0 d) 133 (30 d) 129 (60 d) 126 (90 d) 123 (120 d) 120 (150 d) 115 (180 d)

(25) Copeptin >40 pmol/L:

(26) n=27 (0 d) 21 (30 d) 16 (60 d) 16 (90 d) 15 (120 d) 13 (150 d) 12 (180 d)