WO2008089155A2 - Dosages d'un biomarqueur pour diagnostiquer des infections dans des pays en voie de développement - Google Patents

Dosages d'un biomarqueur pour diagnostiquer des infections dans des pays en voie de développement Download PDF

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Publication number
WO2008089155A2
WO2008089155A2 PCT/US2008/051021 US2008051021W WO2008089155A2 WO 2008089155 A2 WO2008089155 A2 WO 2008089155A2 US 2008051021 W US2008051021 W US 2008051021W WO 2008089155 A2 WO2008089155 A2 WO 2008089155A2
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Prior art keywords
malaria
patient
epo
blood
diagnostic assay
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PCT/US2008/051021
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English (en)
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WO2008089155A3 (fr
Inventor
Douglas A. Holtzman
Anna Roca
Pedro L. Alonso
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Holtzman Douglas A
Anna Roca
Alonso Pedro L
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Publication of WO2008089155A2 publication Critical patent/WO2008089155A2/fr
Publication of WO2008089155A3 publication Critical patent/WO2008089155A3/fr

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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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/746—Erythropoetin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Infectious diseases continue to have a major impact on the health of populations in the developing world. Malaria remains a devastating global health problem, affecting close to 40% of the world population. After attempts to eradicate the disease the 1960's, malaria has resurged once again, affecting a large portion of the developing world. According to the World Health Organization, worldwide, 300- 500 million people contract malaria each year, resulting in 1 to 3 million deaths annually, most of which are children in sub-Saharan Africa.
  • Malaria is caused by intraerythrocytic protozoa of the genus Plasmodium. Humans can be infected with P. falciparum, P. vivax, P. ovale, and P. malariae. Severe malaria is almost exclusively caused by P. falciparum. Plasmodia are primarily transmitted by the bite of an infected female Anopheles mosquito, but can also occur by exposure to infected blood, either congenitally or by transfusion.
  • sporozoites When sporozoites are inoculated into the bloodstream, they enter hepatocytes within hours of their host invasion and begin to divide into exoerythrocytic merozoites. The release of merozoites from the liver usually takes approximately 10-14 days, whereupon the parasite begins to replicate in the red blood cells. Once inside a red blood cell, the parasite begins to multiply and eventually causes the host cell to lyse, releasing the swarm of merozoites into the blood stream, ready to infect the next blood cell. The duration of each cycle is about 48 hours.
  • non-severe malaria the infected individual is ill; in cases of severe malaria the infected individual's life is at risk. In addition, multiple exposures to the malaria parasite can lead to sufficient immunity where the human can harbor parasites without noticeable clinical symptoms. Such an individual is said to be "parasitemic" without having malaria.
  • Clinical symptoms of malaria can include headache, fever, chills, diaphoresis, nausea, vomiting, extreme weakness and impaired consciousness. In laboratory results, the erythrocyte sedimentation rate, C-reactive protein, and procalcitonin are often elevated. Manifestations of severe malaria may additionally include cerebral malaria, severe anemia, hyperpyrexia, acute renal failure, pulmonary adema, hyperparasitemia, and onset of additional associated infections. Patients with severe malaria should be treated on an in-patient basis, in an intensive care unit. Clinical deterioration to severe malaria usually occurs 3-7 days after fever onset. In tropical countries with a high transmission of malaria, severe malaria is predominantly a disease of children under the age of 5. [0008] Settings with no laboratory infrastructure offer the greatest technical challenges for diagnostic test developers.
  • the challenge is to create a test that is easy to transport, store, and administer, and which rapidly provides accurate, easy to interpret results. This challenge is further complicated by the lack of clean water, dependable electricity and trained personnel. To be successfully used in these settings, tests must also be inexpensive and capable of withstanding the grueling environmental conditions.
  • Rapid diagnostic tests or malaria rapid diagnostic devices (MRDDs), such as lateral flow immunochromatographic devices, sometimes referred to as "dipsticks," are often used in rural test centers to rapidly detect species-specific parasite antigens targeting, for example, the histidine-hch protein-2 of P. falciparum or a parasite specific lactate dehydrogenase. These antigens are present in the blood of infected patients.
  • a color change through the use of colohmethc detection techniques such as colloidal gold or colored latex, on the absorbing nitrocellulose strip signifies the presence of parasite antigen.
  • the RDT may detect from one to all four species of malaria parasite which infect humans, depending on the number of antigens it is designed to detect.
  • RDT sensitivity can be influenced by the species of the parasite, the number of parasites present, the care employed in the storage and handling of the device, the method of administration and interpretation of the test, parasite viability, and the antigen used. Although RDT tests may enhance diagnostic speed and ease of use, they have low sensitivity below 100 parasites/ ⁇ l and may show a false negative in patients with high parasitemia.
  • CSF Colony-Stimulating Factors
  • G-CSF Granulocyte CSF
  • M-CSF Macrophage CSF
  • GM-CSF Granulocyte/Macrophage CSF
  • IL-3 lnterleukin 3
  • Some immunological responses are pathogen-specific. For instance, certain intracellular viral infections cause the activation of subsets of T-cells, while other infections lead to B-cell maturation, antibody production and/or antibody- mediated protective mechanisms like phagocytosis and complement-mediated lysis. As a result, cytokine blood levels may have different profiles depending on the etiology of the infection. In particular, G-CSF levels increase in response to certain bacterial infections that cause a high neutrophil turnover. Several studies have investigated the diagnostic use of G-CSF to distinguish between bacterial and viral pneumonia. It has been found that G-CSF blood levels higher than 400pg/ml were suggestive of bacterial pneumonia. Moreover, P.
  • EPO erythropoietin
  • PCT procalcitonin
  • a study conducted in South Africa has suggested that an increased blood level of PCT is suggestive of bacterial infections. Therefore, PCT could be potentially used to differentiate between bacterial and viral infections. Malaria may also cause an increase of that protein, but, the use of the PCT blood level as a means to identify bacterial infections has not been evaluated in malaria endemic areas.
  • G-CSF may be a used as a biomarker for the differential diagnosis of children presenting with fever and clinical pneumonia.
  • Geometric mean (GM) of G-CSF blood levels were substantially increased in children having pneumococcal bacteremia when compared to that of children with malaria parasitemia and no bacteremia. Similar comparisons were found between gram negative bacteremias and malaria.
  • One embodiment of the present claims provide a novel and improved use of a diagnostic assay system for differentiating a patient having severe malaria requiring hospitalization from a patient having a less severe form of malaria where hospitalization is not required.
  • the present diagnostic assay system includes measuring the patient's blood erythropoietin (EPO) levels and comparing the patient's blood EPO levels to a standard value, wherein blood EPO levels above the standard value correlate to that of a patient with severe malaria, and wherein blood EPO levels below the standard value correlate to patients having less severe forms of malaria, and wherein only patients having EPO blood levels equal to or greater than the standard value require hospitalization.
  • EPO blood erythropoietin
  • the present claims provide a novel use of a diagnostic assay system for differentiating a patient having severe malaria from a patient having bacterial pneumonia, comprising measuring a patient's blood EPO level and comparing the patient's blood EPO level to a standard value. If the patient's blood EPO level is above the standard value, then it correlates to a person having severe malaria. If the blood EPO level is below the standard value, then the value correlates with patients having bacterial pneumonia.
  • the present claims provide a novel use of a diagnostic assay system for differentiating a patient having severe malaria from a patient having a non-malarial febrile disease comprising measuring a patient's blood EPO levels and comparing the patient's blood EPO levels to a standard value, wherein blood EPO levels above the standard value correlate to a patient having severe malaria and blood EPO levels below the standard value correlate with patients having non- malarial febrile diseases.
  • the diagnostic assay system will use Enzyme-Linked Immunosorbent Assay (ELISA) to measure blood EPO levels.
  • the diagnostic assay system will use Polymerase Chain Reaction assay (PCR) to measure EPO blood levels.
  • the diagnostic assay system will use lateral flow technology to measure blood EPO levels.
  • the diagnostic assay system will use flow-through technology to measure blood EPO levels.
  • the diagnostic assay system will use latex bead technology to measure blood EPO levels.
  • the diagnostic assay system will use piezoelectric technology to measure blood EPO levels.
  • the diagnostic assay system will use mass spectrometry to measure blood EPO levels. BRIEF DESCRIPTION OF THE DRAWINGS
  • Figure 1 depicts the distribution of patient erythropoietin (EPO) blood levels in Groupi , Group2, Group 3, and Group 5, using the diagnostic assay systems herein disclosed.
  • Group 1 is the control group, consisting of children recruited from the community with no fever, no signs / symptoms of illness and a negative malaria parasitemia.
  • Group 2 is the viral pneumonia group, consisting of children with infiltrates other than consolidation in the chest x-ray, negative blood cultures, negative for malaria parasitemia and positive Polymerase Chain Reaction assay (PCR) for a respiratory virus.
  • Group 3 is the bacterial pneumonia group, consisting of children with clinically severe pneumonia, consolidation in their chest x- ray, positive blood culture, and negative malaria parasitemia.
  • Group 5 is the inpatient malaria group, consisting of children with respiratory distress who have tested positive for malaria parasitemia, have a normal chest x-ray, negative blood culture, and have been diagnosed with malaria by an attending pediatrician.
  • the EPO blood levels are measured in unit per liter. Median, 25 th and 75 th percentiles are indicated.
  • Figure 2 depicts the distribution of patient EPO blood levels in Groups 1 through 6, using the diagnostic assay systems herein disclosed.
  • Group 1 is the control group, consisting of children recruited from the community with no fever, no signs / symptoms of illness and a negative malaria parasitemia.
  • Group 2 is the group consisting of children with infiltrates other than consolidation in the chest x-ray, negative blood cultures, negative for malaria parasitemia and positive PCR for a respiratory virus.
  • Group 3 is the group consisting of in-patient children with consolidation in their chest x-ray, positive blood culture, and negative malaria parasitemia.
  • Group 4 is the group consisting of out-patient children with consolidation in their chest x-ray and negative malaria parasitemia.
  • Group 5 is the in-patient malaria group, consisting of children with respiratory distress who have tested positive for malaria parasitemia, have a normal chest x-ray and negative blood culture.
  • Group 6 is the group consisting of out-patient children who have tested negative for bacterial cultures an positive for malaria, but have less severe symptoms than those children requiring hospitalization.
  • the EPO blood levels are measured in unit per liter. Median, 25 th and 75 th percentiles are indicated.
  • Blood level is a measure of the total amount of erythropoietin in patient blood, whether the sample is whole blood, serum, or plasma.
  • Analyte is defined as the glycoprotein or cytokine that is being measured in the diagnostic assay system.
  • Diagnostic assay system is defined as the system used to differentiate severe malaria patients from other patients with febrile diseases.
  • Severe malaria is defined as a malarial infection that requires hospitalization, wherein parasitemia is more than 5%, and which is often accompanied by hyperpyrexia, cerebral malaria, pulmonary edema, and renal and/or liver malfunction.
  • the presently disclosed diagnostic assay systems use erythropoietin (EPO) to differentiate between a patient having severe malaria requiring hospitalization from a patient with less severe malaria or a patient with another non- malaria febrile disease.
  • EPO erythropoietin
  • the present disclosure describes the use of a diagnostic assay system for differentiating those malarial patients requiring hospitalization and immediate attention from those with less severe infections, not requiring hospitalization.
  • the diagnostic assay system includes a flow device or other analyte detecting and measuring assay capable of detecting levels of EPO in a blood sample.
  • the diagnostic assay system may be used by healthcare providers to distinguish severe malaria from non-severe malaria and other non-malaria febrile diseases, such as bacterial or viral pneumonia.
  • the present disclosure may include an assay for detecting and measuring blood EPO levels using, for example, ELISA, lateral flow technology, flow-through technology, latex bead technology, piezoelectric technology, or mass spectrometry.
  • the diagnostic assay system may use various detection techniques, including, but not limited to spectral, colorimethc, fluohmetric, and electrophoretic analysis. Detection of analyte using any of the foregoing techniques provides information as to the amount of analyte present in the blood sample, which can be compared to the standard value and used to distinguish patients having severe malaria and requiring hospitalization from those having a less severe form of malaria and not requiring hospitalization.
  • the present disclosure may include an assay for detecting and measuring the blood levels of EPO which may include flow-through and/or lateral flow diagnostic technology, often used in determining the levels of a particular protein in a sample.
  • the flow-through and/or lateral flow diagnostic technology may include the following steps: (1 ) obtaining a sample from the subject being diagnosed, (2) contacting the sample with a particular membrane, wherein the subject analyte of interest is bound, and (3) a method of detection is used to determine the presence and quantity of analyte present in the subject sample.
  • the present disclosure describes a diagnostic assay system wherein techniques described in Forney et al. and Makler may be used to diagnose and differentiate severe malaria requiring hospitalization from less severe malaria. It has further been discovered that the techniques described in Forney et al. and Makler may be used to differentiate patients with severe malaria from patients with other non-malarial febrile diseases, such as pneumonia and diarrhea.
  • the present embodiment provides a diagnostic assay system that may include techniques for measuring and detecting EPO.
  • Lee et al. U.S. Pat. No. 7,312,089, is herein incorporated by reference, particularly with respect to its description of techniques for detecting and measuring the amounts of EPO in a blood sample. Techniques like those described in Lee et al. are well-known by those skilled in the art. It has been discovered that these techniques for detecting blood EPO levels may be used to differentiate patients with severe malaria requiring hospitalization from those with less severe malaria. It has further been discovered that the techniques described in Lee et al. may be used to diagnose and differentiate patients with severe malaria from patients with other non-malarial febrile diseases, such as pneumonia and diarrhea.
  • the present embodiment provides a diagnostic assay system that may include an enzyme-linked immunosorbent assay for measuring EPO blood levels, similar to that described in "Alpco Diagnostic EPO EIA Protocol” (www.alpco.com) and Fibi et al., U.S. Pat. No. 5,712,370, herein incorporated by reference.
  • the present embodiment provides a diagnostic assay system that may include latex bead suspension and flow cytometry techniques, similar to those described in Hechinger et al., U.S. Pat. No. 6,159,748, herein incorporated by reference, particularly with respect to its description of methods of detecting antigens in a sample solution.
  • the present disclosure also provides a diagnostic assay system that may include a piezoelectric chemical sensing device, similar to that described in Josse et a/., U.S. Pat. No. 5,852,229, herein incorporated by reference, particularly with respect to its description of a device used to measure concentrations of a particular analyte.
  • Group 1 is the control group, consisting of children recruited from the community with no fever, no signs / symptoms of illness and a negative malaria parasitemia.
  • Group 2 is the viral pneumonia group, consisting of children with infiltrates other than consolidation in the chest x-ray, negative blood cultures, negative for malaria parasitemia and positive PCR for a respiratory virus.
  • Group 3 is the bacterial pneumonia group, consisting of children with clinically severe pneumonia, consolidation in their chest x-ray, positive blood culture, and negative malaria parasitemia.
  • Group 5 is the in-patient malaria group, consisting of children with respiratory distress who have tested positive for malaria parasitemia, have a normal chest x-ray, negative blood culture, and have been diagnosed with malaria by an attending pediatrician.
  • Figure 1 depicts the distribution of patient EPO blood levels using the diagnostic assay systems herein disclosed.
  • the EPO blood levels are measured in unit per liter. Median, 25 th and 75 th percentiles are indicated. EPO blood levels are significantly elevated severe malaria patients and may be used to differentiate patients with severe malaria, requiring hospitalization, from those with no fever as well as from those with bacterial or viral pneumonia. Median EPO blood levels for the Group 5 is 510.6 U/L, almost 7 times higher than the median EPO blood levels for any other group and 28 times higher than the median for the control group. Table 1 depicts a summary of the resulting data.
  • Group 1 is the control group, consisting of children recruited from the community with no fever, no signs / symptoms of illness and a negative malaria parasitemia.
  • Group 2 is the group consisting of children with infiltrates other than consolidation in the chest x-ray, negative blood cultures, negative for malaria parasitemia and positive PCR for a respiratory virus.
  • Group 3 is the group consisting of in-patient children with consolidation in their chest x-ray, positive blood culture, and negative malaria parasitemia.
  • Group 4 is the group consisting of out-patient children with consolidation in their chest x-ray and negative malaria parasitemia.
  • Group 5 is the in-patient malaria group, consisting of children with respiratory distress who have tested positive for malaria parasitemia, have a normal chest x-ray and negative blood culture.
  • Group 6 is the group consisting of out-patient children who have tested negative for bacterial cultures an positive for malaria, but have less severe symptoms than those children requiring hospitalization.
  • Figure 2 depicts the distribution of patient EPO blood levels using the diagnostic assay systems herein disclosed.
  • the EPO blood levels are measured in unit per liter. Median, 25 th and 75 th percentiles are indicated. EPO blood levels are significantly elevated in patients with severe malaria and may be used to differentiate patients with severe malaria, requiring hospitalization, from those with no fever, those with less severe malaria, not requiring hospitalization, those with bacterial pneumonia or consolidations, and those with viral pneumonia.
  • Median EPO blood levels for the Group 5 group is 12 times higher than the median EPO blood levels for patients with less severe malaria, and 28 times higher than the median for the control group. Table 2 depicts a summary of the resulting data.

Abstract

L'invention concerne des systèmes de dosage pour diagnostic qui utilisent de l'érythropoïétine (EPO) pour différencier un patient souffrant d'un paludisme grave nécessitant une hospitalisation d'un patient souffrant d'un paludisme moins grave ou d'un patient souffrant d'une autre maladie fébrile non paludéenne.
PCT/US2008/051021 2007-01-12 2008-01-14 Dosages d'un biomarqueur pour diagnostiquer des infections dans des pays en voie de développement WO2008089155A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010099607A1 (fr) * 2009-03-02 2010-09-10 Fio Corporation Panneau d'essai de diagnostic pour le diagnostic de la malaria et d'infections bacteriennes graves
US9360476B2 (en) 2006-12-19 2016-06-07 Fio Corporation Microfluidic system and method to test for target molecules in a biological sample
US9459200B2 (en) 2008-08-29 2016-10-04 Fio Corporation Single-use handheld diagnostic test device, and an associated system and method for testing biological and environmental test samples
US9695482B2 (en) 2007-10-12 2017-07-04 Fio Coporation Flow focusing method and system for forming concentrated volumes of microbeads, and microbeads formed further thereto
US9792809B2 (en) 2008-06-25 2017-10-17 Fio Corporation Bio-threat alert system
US9805165B2 (en) 2009-01-13 2017-10-31 Fio Corporation Handheld diagnostic test device and method for use with an electronic device and a test cartridge in a rapid diagnostic test
WO2020261297A1 (fr) * 2019-06-27 2020-12-30 Indian Council Of Medical Research Biomarqueurs de prédiction de gravité de paludisme et méthodes associées

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CHANG K H ET AL: "Malarial anaemia: mechanisms and implications of insufficient erythropoiesis during blood-stage malaria" INTERNATIONAL JOURNAL OF PARASITOLOGY, PERGAMON PRESS, GB, vol. 34, no. 13-14, 1 December 2004 (2004-12-01), pages 1501-1516, XP004665009 ISSN: 0020-7519 *
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9360476B2 (en) 2006-12-19 2016-06-07 Fio Corporation Microfluidic system and method to test for target molecules in a biological sample
US9695482B2 (en) 2007-10-12 2017-07-04 Fio Coporation Flow focusing method and system for forming concentrated volumes of microbeads, and microbeads formed further thereto
US9792809B2 (en) 2008-06-25 2017-10-17 Fio Corporation Bio-threat alert system
US9459200B2 (en) 2008-08-29 2016-10-04 Fio Corporation Single-use handheld diagnostic test device, and an associated system and method for testing biological and environmental test samples
US9945837B2 (en) 2008-08-29 2018-04-17 Fio Corporation Single-use handheld diagnostic test device, and an associated system and method for testing biological and environmental test samples
US9805165B2 (en) 2009-01-13 2017-10-31 Fio Corporation Handheld diagnostic test device and method for use with an electronic device and a test cartridge in a rapid diagnostic test
US11385219B2 (en) 2009-01-13 2022-07-12 Fio Corporation Handheld diagnostic test device and method for use with an electronic device and a test cartridge in a rapid diagnostic test
WO2010099607A1 (fr) * 2009-03-02 2010-09-10 Fio Corporation Panneau d'essai de diagnostic pour le diagnostic de la malaria et d'infections bacteriennes graves
WO2020261297A1 (fr) * 2019-06-27 2020-12-30 Indian Council Of Medical Research Biomarqueurs de prédiction de gravité de paludisme et méthodes associées

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