Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-12-21
2002-05-07
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S005000, C435S091100, C435S091200, C415S195000, C415S197000, C415S211100
Reexamination Certificate
active
06383757
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to diagnostic methods based upon a polymorphism in the Tumor Necrosis Factor beta gene (TNFP&bgr;; also known as Lymphotoxin alpha), more specifically, an adenine (“A”) at the +250 site rather than the usual guanosine (“G”). More specifically, this invention relates to a method for diagnosis of Community Acquired Pneumonia (CAP) and diagnosing pre-disposition or susceptibility to CAP, by screening for the presence of this polymorphism, either alone or in combination with a polymorphism at the 308 locus. The invention also relates to compositions for screening for the polymorphism and improved treatment choices for patients diagnosed with CAP or as being susceptible to CAP by the method of the present invention. Further, this invention relates to identifying and diagnosing pre-disposition for septic shock in patients with CAP.
BACKGROUND OF THE INVENTION
Pneumonia is a common clinical entity, particularly among the elderly. CAP is a major health problem world-wide. In the United States, CAP is the leading cause of death due to infection and the sixth most common cause of death overall. Clinically, CAP exhibits an enormous variety in the severity of presentation, from fulminant septic shock at one end of the spectrum to almost asymptomatic disease at the other. A thorough understanding of the epidemiology and microbiology of Community Acquired Pneumonia (CAP) is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of CAP and in CAP in the elderly. Recent studies have provided new data on risk-factors for mortality in CAP, which can assist the clinician in making decisions about the need for hospital admission. The emergence of antimicrobial resistance in
Streptococcus pneumonia,
the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the American Thoracic Society, the British Thoracic Society, and, most recently, the Infectious Diseases Society of America and others. These guidelines differ in their emphasis on empirical versus pathogenic-specific management.
CAP remains a significant health problem and patients continue to die despite receiving appropriate antibiotic therapy. Modification of the host immune response, both anti- and pro-inflammatory approaches, has yet to live up to the promise of improved outcome. Despite this, there is significant reason for optimism. Some immunomodulatory therapies clearly have efficacy in some patients. As the understanding of the immune response to pneumonia improves, the ability to tailor specific therapies for individual patients will also improve, hopefully avoiding the deleterious effects that have so far prevented the development of an effective immune-based therapy. The possibility of delivering cytokines directly to the lung, is a particularly promising way of achieving the desired pulmonary effect without systemic side effects. Corticosteroids are currently unique in that they have a proven role in the therapy of pneumonia due to
P. carinii.
The development of pathogen specific therapies, such as INF for
L. pneumophila,
based on an improved understanding of host-pathogen interactions, are awaited.
Once respiratory failure has ensued, supportive measures such as patient positioning and differential lung ventilation can improve oxygenation at no additional risk in some patients, particularly those with severe unilateral pneumonia. In facilities where ECMO is available it may be beneficial in selected patients when all other means of providing respiratory support have failed. The role of inhaled NO and partial liquid ventilation is also currently unclear and awaiting further study.
The past 20 years has seen an explosion in knowledge of human immunology and exploration of the therapeutic possibilities is just beginning. The next 10 years promises to finally provide a significant advance in the therapy of pneumonia, the first substantial gain since penicillin.
In light of the prevalence of CAP and the evolution of resistance in the most common bacterial CAP pathogen, physicians advise obtaining specimens for culture of CAP pathogens and analysis of patterns of susceptibility, especially of
S. pneumonia,
in their communities; using antibiotics appropriately and prudently, according to prevailing susceptibilities when empirical treatment is called for; and immunizing susceptible patients with pneumococcal and influenza vaccines. This is because the mortality of patients with CAP approaches or may exceed 20%, compared to less than 1% for patients with non-severe CAP (Fine et al.
New Engl. J. Med.
1997;336:243-250,
British Thoracic Society, Q. J. Med
1987;239:192-220, Niederman et al.
Am. Rev. Resp. Dis.
1993;148:1418-1426). In such cases an ability to improve accuracy of diagnosis of, or predisposition or susceptibility to CAP, would be of distinct advantage and may lead to improved outcomes and lower medical costs for such patients.
TNF acts on many healthy cells in addition to cancer cells. It is important in regulating immune and inflammatory response and plays a large role in septic shock. It is released by a variety of cells including red and white blood cells, cells that line blood vessels, nervous system cells, muscle cells, bone cells, and some tumor cells. Although it was first observed to kill certain tumor cells (sarcoma cells), TNF has been found to help some tumors grow. In addition, TNF can be very toxic to normal cells. Early experiments found that administering TNF caused fever and loss of appetite. TNF also has been shown to affect the metabolism of many cell types, causing them to need more oxygen. It has been found to play a role in many autoimmune diseases, such as rheumatoid arthritis and myasthenia gravis. Certain viral and bacterial infections can cause healthy cells to produce elevated levels of TNF.
It is a surprising feature of the present invention to be able to diagnose the presence of CAP and the predisposition or susceptibility to CAP by the method of the present invention.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to improve diagnosis of CAP. It is a particular object of the invention to provide a method of diagnosis of predisposition or susceptibility to CAP. A further object is to provide, following such diagnosis, a method of identifying patients for alternative management of CAP before the disease becomes significantly established. Thus, the invention also relates to compositions for screening for the TNF&bgr; polymorphism at the +250 site and improved treatment choices for patients diagnosed with CAP or as being susceptible to CAP by the method of the present invention. A further object of the present invention is to identify and diagnose CAP patients at an increased risk for CAP associated septic shock.
Other preferred embodiments of the present invention will be apparent to one of ordinary skill in light of the following description of the invention and of the claims.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the invention provides a method of diagnosing a disease associated with a genetic polymorphism (adenine (“A”) at the +250 site rather than the usual guanosine (“G”)) in a TNF&bgr; gene in an animal predisposed or susceptible to said disease, said method comprising determining the genotype of TNF&bgr; in said animal. The first aspect of the invention further provides a method of identifying an animal predisposed or susceptible to a disease associated with a genetic polymorphism in a TNF&bgr; gene, said method comprising determining the genotype of said TNF&bgr; gene in said animal. In an embodiment of the invention, the method of diagnosis is to screen for an individual at r
Waterer Grant William
Wunderink Richard Glenn
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