EP1882945A1 - Vorrichtungen und Verfahren zur Differentierung zwischen herz- und lungenbedingten Ursachen für akute Atemnot - Google Patents

Vorrichtungen und Verfahren zur Differentierung zwischen herz- und lungenbedingten Ursachen für akute Atemnot Download PDF

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Publication number
EP1882945A1
EP1882945A1 EP06118090A EP06118090A EP1882945A1 EP 1882945 A1 EP1882945 A1 EP 1882945A1 EP 06118090 A EP06118090 A EP 06118090A EP 06118090 A EP06118090 A EP 06118090A EP 1882945 A1 EP1882945 A1 EP 1882945A1
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Prior art keywords
pulmonary
cardiovascular
pulmonary disease
subject
amount
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EP06118090A
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English (en)
French (fr)
Inventor
Georg Prof. Dr. Hess
Andrea Dr. Horsch
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F Hoffmann La Roche AG
Roche Diagnostics GmbH
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F Hoffmann La Roche AG
Roche Diagnostics GmbH
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Priority to EP06118090A priority Critical patent/EP1882945A1/de
Priority to CA002593304A priority patent/CA2593304A1/en
Priority to US11/780,560 priority patent/US7892844B2/en
Priority to EP07113008A priority patent/EP1882947A1/de
Priority to JP2007196068A priority patent/JP4731525B2/ja
Priority to CNA2007101596680A priority patent/CN101173928A/zh
Publication of EP1882945A1 publication Critical patent/EP1882945A1/de
Withdrawn legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Brain natriuretic peptide [BNP, proBNP]; Cardionatrin; Cardiodilatin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/785—Alveolar surfactant peptides; Pulmonary surfactant peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders

Definitions

  • a typical symptom for cardiovascular complications, in particular, for an acute cardiovascular event or a more severe chronic heart failure is shortness of breath (dyspnea).
  • dyspnea may have various causes including cardiovascular complications and non-cardiovascular pulmonary diseases.
  • WO99/13337 discloses that surfactant proteins may be used as a biomarker for several specific pulmonary diseases including acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • WO2004/077056 it is disclosed that systemic levels of surfactant proteins may be used as markers for heart failure.
  • the disclosed techniques do not allow for a differential diagnosis of the cause of the elevated levels of the surfactant proteins.
  • pulmonary diseases or damages may also result in increased systemic levels of said proteins ( Doyle 1997, Am J Respir Crit Care Med Vol. 156: 1217-1229 ).
  • the disclosed methods shall inevitably produce false positive diagnostic results which in turn result in an inappropriate therapy ( Svendstrup Nielsen, 2004, The European Journal of Heart Failure 6: 63-70 ).
  • NT-proBNP N-terminal brain natriuretic Peptide
  • NYHA New York Hear Association
  • NT-proBNP has been also described together with seven additional parameters as an indicator for acute heart failure in patients exhibiting dyspnoea ( Baggish 2005, American Heart Journal, 151:48-54 ).
  • the present invention relates to a method for differentiating in a subject suffering from acute shortness of breath (dyspnea) between (i) a pulmonary disease, (ii) a cardiovascular complication, (iii) a cardiovascular complication accompanied by a pulmonary disease or (iv) acute dyspnea without cardiovascular or pulmonary causes comprising the steps of:
  • the term "differentiating" as used herein means to distinguish between a subject which suffers from (i) a pulmonary disease, (ii) a cardiovascular complication, (iii) a cardiovascular complication accompanied by a pulmonary disease or (iv) acute dyspnea without cardiovascular or pulmonary causes under conditions where the subjects suffering from said disease show essentially the same symptoms, i.e. acute shortness of breath.
  • the term as used herein preferably, includes differentially diagnosing a pulmonary disease, a cardiovascular complication showing pulmonary symptoms, a cardiovascular complication accompanied by a pulmonary disease or acute dyspnea without cardiovascular or pulmonary causes.
  • Diagnosing refers to assessing the probability according to which a subject suffers from the diseases referred to in this specification. As will be understood by those skilled in the art, such an assessment is usually not intended to be correct for 100% of the subjects to be diagnosed. The term, however, requires that a statistically significant portion of subjects can be diagnosed to suffer from the said disease (e.g. a cohort in a cohort study). Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann-Whitney test etc..
  • Diagnosing according to the present invention also includes monitoring, confirmation, subclassification and prediction of the relevant disease, symptoms or risks therefor.
  • Monitoring relates to keeping track of an already diagnosed disease, or complication, e.g. to analyze the progression of the disease or the influence of a particular treatment on the progression of disease or complication.
  • Confirmation relates to the strengthening or substantiating a diagnosis already performed using other indicators or markers.
  • Subclassification relates to further defining a diagnosis according to different subclasses of the diagnosed disease, e.g. defining according to mild and severe forms of the disease.
  • Prediction relates to prognosing a disease or complication before other symptoms or markers have become evident or have become significantly altered.
  • acute dyspnea persists no longer than 2 weeks from the acute onset, while chronic dyspnea is characterized as persisting for a periode of time longer than 2 weeks. Furthermore, acute dyspnea is, usually, progressively worsening.
  • cardiovascular diseases which cause heart failure in addition to the aforementioned acute cardiovascular events, such as congenital or acquired heart valve diseases or disorders, myocarditis, myocardiopathy, amyloidosis or hemochromatosis.
  • cardiovascular diseases are thrombosis, preferably arterial thrombosis, or diseases causing blood vessel calcification, preferably atherosclerosis, as well as stroke.
  • the individuals suffering from a cardiovascular complication may show clinical symptoms (e.g. dyspnea, chest pain, see also NYHA classification below).
  • symptoms of cardiovascular diseases have been classified into a functional classification system according to the New York Heart Association (NYHA).
  • NYHA New York Heart Association
  • Patients of Class I have no obvious symptoms of cardiovascular disease.
  • Physical activity is not limited, and ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea.
  • Patients of class II have slight limitation of physical activity. They are comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.
  • Patients of class III show a marked limitation of physical activity. They are comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.
  • LVEF left ventricular ejection fraction
  • a subject suffering from a cardiovascular complication and exhibiting acute dyspnea in accordance with the present invention can be allocated to an intermediated NYHA class, preferably, to NYHA class I, II or III and, most preferably, to NYHA class II.
  • a cardiovascular complication accompanied by a pulmonary disease it is meant that the subject shall suffer from a cardiovascular complication and from a pulmonary disease. It is to be understood that the two diseases or disorders may appear independently, i.e. without one causing the other. However, cases in which a primary cardiovascular complication as referred to herein causes a secondary pulmonary diseases and vice versa are also, preferably, encompassed from the above expression.
  • acute dyspnea may, whatsoever, be observed in patients which neither suffer from cardiovascular complications nor from pulmonary diseases. Such cases shall be comprised by the term "acute dyspnea without cardiovascular or pulmonary causes" for the purpose of the present invention.
  • Preferred non-cardiovascular and non-pulmonar causes of acute shortness of breath are, preferably, obesity, high body weight, an untrained or poorly trained physical condition of the subject, psychological conditions such as anxiety states.
  • Determining the amount of a natriuretic peptide or a pulmonary surfactant protein relates to measuring the amount or concentration, preferably semi-quantitatively or quantitatively. Measuring can be done directly or indirectly. Direct measuring relates to measuring the amount or concentration of the natriuretic peptide or the pulmonary surfactant protein based on a signal which is obtained from the natriuretic peptide or the pulmonary surfactant protein itself and the intensity of which directly correlates with the number of molecules of the peptide present in the sample.
  • the method for determining the amount of a natriuretic peptide or a pulmonary surfactant protein comprises the steps of (a) contacting a cell capable of eliciting a cellular response the intensity of which is indicative of the amount of the peptide with the peptide for an adequate period of time, (b) measuring the cellular response.
  • the sample or processed sample is, preferably, added to a cell culture and an internal or external cellular response is measured.
  • the cellular response may include the measurable expression of a reporter gene or the secretion of a substance, e.g. a peptide, polypeptide, or a small molecule.
  • the expression or substance shall generate an intensity signal which correlates to the amount of the peptide.
  • the method for determining the amount of a natriuretic peptide or a pulmonary surfactant protein comprises the step of measuring a specific intensity signal obtainable from the natriuretic peptide or a pulmonary surfactant protein in the sample.
  • such a signal may be the signal intensity observed at an m/z variable specific for the natriuretic peptide or a pulmonary surfactant protein observed in mass spectra or a NMR spectrum specific for the natriuretic peptide or a pulmonary surfactant protein.
  • the method for determining the amount of a natriuretic peptide may also preferably comprise the steps of (a) contacting the peptide with a specific ligand, (b) (optionally) removing non-bound ligand, (c) measuring the amount of bound ligand.
  • the bound ligand will generate an intensity signal.
  • Binding according to the present invention includes both covalent and non-covalent binding.
  • a ligand according to the present invention can be any compound, e.g., a peptide, polypeptide, nucleic acid, or small molecule, binding to the natriuretic peptide or the pulmonary surfactant protein described herein.
  • Antibodies as referred to herein include both polyclonal and monoclonal antibodies, as well as fragments thereof, such as Fv, Fab and F(ab) 2 fragments that are capable of binding antigen or hapten.
  • the present invention also includes humanized hybrid antibodies wherein amino acid sequences of a non-human donor antibody exhibiting a desired antigen-specificity are combined with sequences of a human acceptor antibody.
  • the donor sequences will usually include at least the antigen-binding amino acid residues of the donor but may comprise other structurally and/or functionally relevant amino acid residues of the donor antibody as well.
  • Such hybrids can be prepared by several methods well known in the art.
  • the ligand or agent binds specifically to the natriuretic peptide.
  • Specific binding according to the present invention means that the ligand or agent should not bind substantially to ("cross-react" with) another peptide, polypeptide or substance present in the sample to be analyzed.
  • the specifically bound natriuretic peptide should be bound with at least 3 times higher, more preferably at least 10 times higher and even more preferably at least 50 times higher affinity than any other relevant peptide or polypeptide.
  • Non-specific binding may be tolerable, if it can still be distinguished and measured unequivocally, e.g. according to its size on a Western Blot, or by its relatively higher abundance in the sample. Binding of the ligand can be measured by any method known in the art. Preferably, said method is semiquantitative or quantitative. Suitable methods are described in the following.
  • binding of a ligand may be measured directly, e.g. by NMR, mass spectrometry or surface plasmon resonance.
  • an enzymatic reaction product may be measured (e.g. the amount of a protease can be measured by measuring the amount of cleaved substrate, e.g. on a Western Blot).
  • the ligand may be coupled covalently or non-covalently to a label allowing detection and measurement of the ligand. Labeling may be done by direct or indirect methods. Direct labeling involves coupling of the label directly (covalently or non-covalently) to the ligand. Indirect labeling involves binding (covalently or non-covalently) of a secondary ligand to the first ligand. The secondary ligand should specifically bind to the first ligand. Said secondary ligand may be coupled with a suitable label and/or be the target (receptor) of tertiary ligand binding to the secondary ligand.
  • the tag is preferably at the N-terminus and/or C-terminus.
  • Suitable labels are any labels detectable by an appropriate detection method. Typical labels include gold particles, latex beads, acridan ester, luminol, ruthenium, enzymatically active labels, radioactive labels, magnetic labels ("e.g. magnetic beads", including paramagnetic and superparamagnetic labels), and fluorescent labels.
  • Enzymatically active labels include e.g.
  • Suitable substrates for detection include di-amino-benzidine (DAB), 3,3'-5,5'-tetramethylbenzidine, NBT-BCIP (4-nitro blue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl-phosphate, available as ready-made stock solution from Roche Diagnostics), CDP-StarTM (Amersham Biosciences), ECFTM (Amersham Biosciences).
  • a suitable enzyme-substrate combination may result in a colored reaction product, fluorescence or chemoluminescence, which can be measured according to methods known in the art (e.g.
  • Typical fluorescent labels include fluorescent proteins (such as GFP and its derivatives), Cy3, Cy5, Texas Red, Fluorescein, and the Alexa dyes (e.g. Alexa 568). Further fluorescent labels are available e.g. from Molcular Probes (Oregon). Also the use of quantum dots as fluorescent labels is contemplated.
  • Typical radioactive labels include 35 S, 125 I, 32 P, 33 P and the like. A radioactive label can be detected by any method known and appropriate, e.g. a light-sensitive film or a phosphor imager.
  • Suitable measurement methods according the present invention also include precipitation (particularly immunoprecipitation), electrochemiluminescence (electro-generated chemiluminescence), RIA (radioimmunoassay), ELISA (enzyme-linked immunosorbent assay), sandwich enzyme immune tests, electrochemiluminescence sandwich immunoassays (ECLIA), dissociation-enhanced lanthanide fluoro immuno assay (DELFIA), scintillation proximity assay (SPA), turbidimetry, nephelometry, latex-enhanced turbidimetry or nephelometry, or solid phase immune tests.
  • precipitation particularly immunoprecipitation
  • electrochemiluminescence electrochemiluminescence (electro-generated chemiluminescence)
  • RIA radioimmunoassay
  • ELISA enzyme-linked immunosorbent assay
  • sandwich enzyme immune tests sandwich enzyme immune tests
  • Materials for manufacturing solid supports include, inter alia, commercially available column materials, polystyrene beads, latex beads, magnetic beads, colloid metal particles, glass and/or silicon chips and surfaces, nitrocellulose strips, membranes, sheets, duracytes, wells and walls of reaction trays, plastic tubes etc.
  • the ligand or agent may be bound to many different carriers. Examples of well-known carriers include glass, polystyrene, polyvinyl chloride, polypropylene, polyethylene, polycarbonate, dextran, nylon, amyloses, natural and modified celluloses, polyacrylamides, agaroses, and magnetite.
  • the nature of the carrier can be either soluble or insoluble for the purposes of the invention.
  • values or parameters which are obtained by indirect measurements specified elsewhere in this description e.g., expression levels determined from biological read out systems in response to the natriuretic peptide or the pulmonary surfactant protein or intensity signals obtained from specifically bound ligands. It is to be understood that values correlating to the aforementioned amounts or parameters can also be obtained by all standard mathematical operations.
  • the human proteins are well characterized in the prior art and disclosed, e.g., in Hawgood, 1989, Am J Physiol -Lung Cellular and Molecular Physiology, Vol 257, Issue 2:13-L22 (for all surfactant proteins), Takahashi 2006, Curr Pharm Des, 12(5):589-598 (for SP-A and SP-D), and Kurutz 2002, Biochemistry, 41(30):9627-9636 , Guttentag 1998, Am J Physiol -Lung Cellular and Molecular Physiology, Vol 275, Issue 3:L559-L566 (for SP-B).
  • pulmonary surfactant proteins which are on the amino acid level at least 60 % identical, more preferably at least 70 %, at least 80 %, at least 90 %, at least 95 %, at least 98% or at least 99 % identical, to the human pulmonary surfactant proteins.
  • proteolytic degradation products which are still recognized by the diagnostic means or by ligands directed against the respective full-length peptide.
  • variant polypeptides having amino acid deletions, substitutions, and/or additions compared to the amino acid sequence of a human pulmonary surfactant protein as long as the said polypeptides have pulmonary surfactant protein properties
  • pulmonary surfactant protein properties as referred to herein are immunological and/or biological properties.
  • the pulmonary surfactant protein variants have immunological properties (i.e. epitope composition) comparable to those of the pulmonary surfactant proteins specifically referred to herein.
  • the variants shall be recognizable by the aforementioned means or ligands used for determination of the pulmonary surfactant protein.
  • Variants also include posttranslationally modified pulmonary surfactant proteins such as glycosylated proteins.
  • SP-B may be determined in combination with SP-D or SP-A or both.
  • natriuretic peptide comprises A trial N atriuretic P eptide (ANP)-type and Brain N atriuretic P eptide (BNP)-type peptides and variants thereof having the same predictive potential.
  • Natriuretic peptides according to the present invention comprise ANP-type and BNP-type peptides and variants thereof (see e.g. Bonow, R.O. (1996). New insights into the cardiac natriuretic peptides. Circulation 93: 1946-1950 ).
  • ANP-type peptides comprise pre-proANP, proANP, NT-proANP, and ANP.
  • BNP-type peptides comprise pre-proBNP, proBNP, NT-proBNP, and BNP.
  • the pre-pro peptide (134 amino acids in the case of pre-proBNP) comprises a short signal peptide, which is enzymatically cleaved off to release the pro peptide (108 amino acids in the case of proBNP).
  • the pro peptide is further cleaved into an N-terminal pro peptide (NT-pro peptide, 76 amino acids in case of NT-proBNP) and the active hormone (32 amino acids in the case of BNP, 28 amino acids in the case of ANP).
  • Preferred natriuretic peptides according to the present invention are NT-proANP, ANP, NT-proBNP, BNP, and variants thereof.
  • ANP and BNP are the active hormones and have a shorter half-life than their respective inactive counterparts, NT-proANP and NT-proBNP.
  • BNP is metabolised in the blood, whereas NT-proBNP circulates in the blood as an intact molecule and as such is eliminated renally.
  • the in-vivo half-life of NTproBNP is 120 min longer than that of BNP, which is 20 min ( Smith MW, Espiner EA, Yandle TG, Charles CJ, Richards AM. Delayed metabolism of human brain natriuretic peptide reflects resistance to neutral endopeptidase. J Endocrinol. 2000; 167: 239-46 .).
  • Preanalytics are more robust with NT-proBNP allowing easy transportation of the sample to a central laboratory ( Mueller T, Gegenhuber A, Dieplinger B, Poelz W, Haltmayer M. Long-term stability of endogenous B-type natriuretic peptide (BNP) and amino terminal proBNP (NT-proBNP) in frozen plasma samples. Clin Chem Lab Med 2004; 42: 942-4 .). Blood samples can be stored at room temperature for several days or may be mailed or shipped without recovery loss.
  • NT-proBNP The most preferred natriuretic peptides according to the present invention are NT-proBNP or variants thereof.
  • the human NT-proBNP as referred to in accordance with the present invention is a polypeptide comprising, preferably, 76 amino acids in length corresponding to the N-terminal portion of the human NT-proBNP molecule.
  • the structure of the human BNP and NT-proBNP has been described already in detail in the prior art, e.g., WO 02/089657 , WO 02/083913 , Bonow 1996, New Insights into the cardiac natriuretic peptides. Circulation 93: 1946-1950 .
  • human NT-proBNP as used herein is human NT-proBNP as disclosed in EP 0 648 228 B1 .
  • These prior art documents are herewith incorporated by reference with respect to the specific sequences of NT-proBNP and variants thereof disclosed therein.
  • the NT-proBNP referred to in accordance with the present invention further encompasses allelic and other variants of said specific sequence for human NT-proBNP discussed above.
  • variant polypeptides which are on the amino acid level at least 60 % identical, more preferably at least 70 %, at least 80 %, at least 90 %, at least 95 %, at least 98% or at least 99 % identical, to human NT-proBNP.
  • Substantially similar and also envisaged are proteolytic degradation products which are still recognized by the diagnostic means or by ligands directed against the respective full-length peptide.
  • variant polypeptides having amino acid deletions, substitutions, and/or additions compared to the amino acid sequence of human NT-proBNP as long as the said polypeptides have NT-proBNP properties.
  • NT-proBNP properties as referred to herein are immunological and/or biological properties.
  • the NT-proBNP variants have immunological properties (i.e. epitope composition) comparable to those of NT-proBNP.
  • the variants shall be specifically recognizable (i. e. without cross reactions) by the aforementioned means or ligands used for determination of the amount of the natriuretic peptides.
  • sample refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ.
  • Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum or urine.
  • Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy.
  • Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting.
  • Comparing as used herein encompasses comparing the amount of the natriuretic peptide or the pulmonary surfactant protein comprised by the sample to be analyzed with an amount of a suitable reference source specified below in this description. It is to be understood that comparing as used herein refers to a comparison of corresponding parameters or values, e.g., an absolute amount is compared to an absolute reference amount while a concentration is compared to a reference concentration or an intensity signal obtained from a test sample is compared to the same type of intensity signal of a reference sample.
  • the comparison referred to in step (b) of the method of the present invention may be carried out manually or computer assisted.
  • the value of the determined amount may be compared to values corresponding to suitable references which are stored in a database by a computer program.
  • the computer program may further evaluate the result of the comparison, i.e. automatically providing a differential diagnosis for the diseases referred to herein in a suitable output format.
  • the term "reference amount" as used herein refers to an amount which allows assessing whether a subject suffers from any one of the aforementioned diseases or disorders by a comparison as referred to above. Accordingly, the reference may either be derived from a subject suffering from (i) a pulmonary disease, (ii) a cardiovascular complication, (iii) a cardiovascular complication accompanied by a pulmonary disease or (iv) acute dyspnea without cardiovascular or pulmonary causes, i.e. from a healthy subject with respect to cardiovascular complications and pulmonary diseases.
  • an amount of a peptide or protein in a sample of a test subject being essentially identical to said reference amount shall be indicative for the respective disease or combination of diseases. If a reference from a healthy subject is used, an amount of a peptide or protein in a sample of a test subject which significantly differs from the reference (i.e. from the normal values of the surfactant proteins and natriuretic peptides referred to herein) shall indicate a disease.
  • the reference amount applicable for an individual subject may vary depending on various physiological parameters such as age, gender, or subpopulation. Thus, a suitable reference amount may be determined by the method of the present invention from a reference sample to be analyzed together, i.e. simultaneously or subsequently, with the test sample.
  • the subject in case elevated amounts for the pulmonary surfactant protein are determined but no or only weak elevated amounts of the natriuretic peptides are determined, the subject shall merely suffer from a pulmonary disease. In case the determined amounts of the natriuretic peptide and the surfactant protein are both elevated with respect to the normal ranges, the subject shall suffer from a cardiovascular complication. If the amount of the natriuretic peptide is significantly strong elevated and the amount of the surfactant protein is elevated, too, the subject shall suffer from a cardiovascular complication accompanied by a pulmonary disease.
  • the normal physiological (i. e. not elevated) range for the amounts of the surfactant protein, preferably for SP-B, is 12,000 to 20,000 ng/ml, preferably 20,000 ng/ml.
  • the normal physiological (i. e. not elevated range) for natriuretic peptides and in particular for NT-proBNP is 80 to 150 pg/ml, preferably 125 pg/ml.
  • natriuretic peptides and, preferably, of NT-proBNP which are larger than or equal to 3,200 pg/ml. It is to be understood that the aforementioned amounts may vary due to statistics and errors of measurement.
  • the amount of pulmonary surfactant protein in combination with the amount of NT-pro BNP present in a sample of a subject showing pulmonary symptoms, in particular, acute shortness of breath allow for a differential diagnosis with respect to the cause of the said symptoms. Thanks to the present invention, subjects and in particular emergency patients can be more readily and reliably diagnosed and subsequently treated according to the result of the said differential diagnosis.
  • the pulmonary disease of the cardiovascular complication accompanied by a pulmonary disease is caused by the cardiovascular complication.
  • the cardiovascular complication of (iii) is caused by the pulmonary disease.
  • the pulmonary disease of (iii) is independent on the cardiovascular complication.
  • a reference amount less than 125 pg/ml for the natriuretic peptide and a reference amount larger than 20,000 ng/ml for a pulmonary surfactant protein are indicative for (i) a pulmonary disease.
  • a reference amount larger than 125 pg/ml but less than 3,200 pg/ml for the natriuretic peptide and a reference amount less than 20,000 ng/ml for a pulmonary surfactant protein are indicative for (ii) a cardiovascular complication.
  • a reference amount of larger than 3,200 pg/ml for the natriuretic peptide and a reference amount lager than 20,000 ng/ml for a pulmonary surfactant protein are indicative for (iii) a pulmonary disease accompanied by a cardiovascular complication.
  • said sample is blood, plasma, serum or urine.
  • said natriuretic peptide is NT-proBNP.
  • said pulmonary surfactant protein is SP-B, SP-D or SP-A.
  • said subject is a human.
  • the present invention relates to a device for differentiating between (i) a pulmonary disease, (ii) a cardiovascular complication showing pulmonary symptoms, (iii) a cardiovascular complication accompanied by a pulmonary disease or (iv) acute dyspnea without cardiovascular or pulmonary causes in a subject exhibiting acute dyspnea comprising
  • the term "device” as used herein relates to a system of means comprising at least the aforementioned means operatively linked to each other as to allow the prediction.
  • Preferred means for determining the amount of the natriuretic peptides or the pulmonary surfactant protein and means for carrying out the comparison are disclosed above in connection with the method of the invention. How to link the means in an operating manner will depend on the type of means included into the device. For example, where means for automatically determining the amount of the peptides are applied, the data obtained by said automatically operating means can be processed by, e.g., a computer program in order to diagnose or distinguish between the diseases referred to herein.
  • the means are comprised by a single device in such a case.
  • Said device may accordingly include an analyzing unit for the measurement of the amount of the peptides in a sample and a computer unit for processing the resulting data for the differential diagnosis.
  • the means for diagnosing may comprise control stripes or tables allocating the determined amount to an amount known to be accompanied with (i) a pulmonary disease, (ii) a cardiovascular complication, (iii) a cardiovascular complication accompanied by a pulmonary disease or (iv) acute dyspnea without cardiovascular or pulmonary causes or a healthy control subject.
  • the test stripes are, preferably, coupled to a ligand which specifically binds to the natriuretic peptide or pulmonary surfactant protein.
  • the strip or device preferably, comprises means for detection of the binding of said peptides to the said ligand.
  • Preferred means for detection are disclosed in connection with embodiments relating to the method of the invention above.
  • the means are operatively linked in that the user of the system brings together the result of the determination of the amount and the diagnostic value thereof due to the instructions and interpretations given in a manual.
  • the means may appear as separate devices in such an embodiment and are, preferably, packaged together as a kit. The person skilled in the art will realize how to link the means without further ado.
  • Preferred devices are those which can be applied without the particular knowledge of a specialized clinician, e.g., test stripes or electronic devices which merely require loading with a sample.
  • the results may be given as output of diagnostic raw data which need interpretation by the medical practitioner.
  • the output of the device are, however, processed diagnostic raw data the interpretation of which does not require a specialized medical practitioner.
  • Further preferred devices comprise the analyzing units/devices (e.g., biosensors, arrays, solid supports coupled to ligands specifically recognizing the natriuretic peptide, Plasmon surface resonace devices, NMR spectrometers, mass- spectrometers etc.) or evaluation units/devices referred to above in accordance with the method of the invention.
  • kit refers to a collection of the aforementioned means, preferably, provided in separately or within a single container.
  • the container also preferably, comprises instructions for carrying out the method of the present invention.
  • a cohort of 214 patients suffering from acute dyspnea has been clinically investigated for the presence of heart failure, pulmonary disease or a combination of both diseases.
  • the allocation of the patients into the three disease groups has been confirmed by clinical examination, ECG and echocardiography.
  • Blood samples of the patients have been analyzed by the prototype SP-B ELISA (Flinders assay protocol for the SP-B amounts and by the Elecsys NT-proBNPTM assay (Roche Diagnostics) for NT-proBNP concentrations.
  • NT-proBNP concentration The result of the determination of the NT-proBNP concentration is shown in Figure 1.
  • Patients suffering from a combination of both diseases show strongly elevated NT-proBNP levels
  • patients suffering from heart failure show elevated NT-proBNP levels.
  • patients suffering from pulmonary disease only show weak elevated or normal NT-proBNP levels.
  • Figure 2 shows the outcome of the determination of the SP-B amount in the different patient groups. Pulmonary diseases or a combination of both diseases show elevated amounts of SP-B. Patients exhibiting acute dyspnea due to non-cardiac and/or non pulmonary causes show no significantly elevated SP-B with respect to the reference values described in the literature.

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CA002593304A CA2593304A1 (en) 2006-07-28 2007-07-09 Means and methods for the differentiation of cardiac and pulmonary causes of acute shortness of breath
US11/780,560 US7892844B2 (en) 2006-07-28 2007-07-20 Differentiation of cardiac and pulmonary causes of acute shortness of breath
EP07113008A EP1882947A1 (de) 2006-07-28 2007-07-24 Mittel und Verfahren zur Unterscheidung von herz- und lungenbedingten Ursachen für akute Atemnot
JP2007196068A JP4731525B2 (ja) 2006-07-28 2007-07-27 心因性と肺因性の急性呼吸窮迫を鑑別する手段と方法
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EP2597466A1 (de) 2012-06-26 2013-05-29 Roche Diagniostics GmbH Mittel und Verfahren zur proSP-B-basierten Diagnose von Alveolenbeschädigung bei Patienten mit pulmonaler Hypertonie
EP2597467A1 (de) 2012-06-26 2013-05-29 Roche Diagniostics GmbH Mittel und Verfahren zur proSP-B-basierten Diagnose von Lungenstauung bei Patienten mit akutem Koronarsyndrom
EP2866033A1 (de) 2013-10-23 2015-04-29 Roche Diagniostics GmbH Differenzialdiagnose von akuter Atemnot auf Basis von c-terminiertem proSP-B, KL-6 und BNP-Peptiden

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