Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1996-07-26
2002-05-07
Swartz, Rodney P (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C424S141100, C424S150100, C424S163100, C424S178100, C435S007100
Reexamination Certificate
active
06383763
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the detection and diagnosis of infection and disease due to the mycobacteria, especially
Mycobacterium tuberculosis
and other mycobacteria commonly associated with disease in immunocompromised patients including those with acquired immunodeficiency syndrome (AIDS). The present invention is suited for rapid screening of large populations for the presence of
M. tuberculosis
carriers, as well as diagnosing and monitoring disease or infection in patients who present at healthcare or public health facilities.
BACKGROUND OF THE INVENTION
Organisms within the genus Mycobacterium include obligate parasites, saprophytes, and opportunistic pathogens. Most species are free-living in soil and water, but for species such as
M. tuberculosis
and
M. leprae,
the causative agents of tuberculosis and leprosy respectively, the major ecological niche is the tissue of humans and other warm-blooded animals.
Despite the fact that most mycobacteria do not cause disease, a relatively small group of organisms within the genus is responsible for a large percentage of human morbidity and mortality worldwide. Tuberculosis remains a major global health problem, with nearly one third of the world's population infected. Indeed, tuberculosis is the leading cause of death due to a single infectious agent. In addition. the World Health Organization estimates that worldwide, there are 8-10 million new cases and over 3 million deaths directly attributed to this disease reported worldwide (A. Kochi, The global tuberculosis situation and the new control strategy of the World Health Organization, Tubercle 72:1-6 [1991]).
M. tuberculosis
is exceptionally easily transmitted, as it is carried in airborne particles termed “droplet nuclei,” produced when a patient with active tuberculosis coughs. These particles are from 1-5&mgr; in size, and are readily suspended in air currents. Infection occurs when droplet nuclei are inhaled and reach the terminal airways of the new host's lungs. Usually, the host immune response limits the multiplication and spread of the organism, although some organisms may remain dormant, but viable, for many years post-infection. Individuals infected with
M. tuberculosis
but without disease, usually have a positive skin test (i.e., with purified protein derivative [PPD]), but are asymptomatic and generally not infectious. However, latently infected individuals have a 10% risk for developing active tuberculosis at some point during their life; the risk is greatest within the first two years post-infection. For HIV-positive individuals, the risk is much greater, with the risk at 10-15% per year for progression to active disease (F. S. Nolte and B. Metchock, “Mycobacterium,” in
Manual of Clinical Microbiology,
Sixth Edition, ASM Press: Washington, [1995],pp. 400-437).
Co-infection with human immunodeficiency virus (HIV) and
M. tuberculosis
has resulted in staggering increases in tuberculosis rates—as much as 200% in the past 4 years, particularly in impoverished countries with few resources available to control this epidemic. Yet even western industrialized countries have reported increases in tuberculosis rates of from 2 to 14% per year during the past decade (World Health Organization TB Programme, quoted in “TB: A Global Emergency,” WHO, 1994). These increases, coupled with the emergence of multi-drug-resistant strains, and the recognition that tuberculosis is one HIV-related opportunistic infection which can be readily transmitted to HIV-uninfected persons, have focused the attention of physicians, researchers, and public health workers on issues related to tuberculosis control, particularly in terms of development of improved vaccines for tuberculosis prevention and improved tests for tuberculosis diagnosis.
In the United States, aggressive approaches to tuberculosis control including isolation of patients in facilities such as sanitoria and the development of drugs effective against
M. tuberculosis
resulted in a steady decline in the incidence of tuberculosis until about 1985, when the trend reversed and the reports of new tuberculosis cases began to increase. If the trend for the years 1980-1984 is used to calculate the number of expected cases, the Centers for Disease Control and Prevention (CDC) estimated that between 1985-1992, approximately 51,000 excess cases have accumulated (D. E. Snider et al., “Global burden of tuberculosis,” in B. R. Bloom (ed.),
Tuberculosis: Pathogenesis, Protection and Control,
American Society for Microbiology, Washington, D.C., [1994], pp. 3-11).
A number of contributory factors are likely to be responsible for the observed increase in tuberculosis cases, including the AIDS pandemic, immigration from areas with high endemicity of tuberculosis, general deterioration of the health care infrastructure, transmission in high-risk environments (e.g., homeless shelters), and the increase in the number of multi-drug resistant
M. tuberculosis
strains (Nolte and Metchock, supra, at p. 400). Unless the effectiveness and availability of methods and drugs to detect and treat tuberculosis do not substantially improve, it is expected that over 30 million deaths and 90 million new cases of tuberculosis will occur in the years between 1990-2000 (Snider et al., at p. 10).
Although it is the major cause, organisms other than
M. tuberculosis
are sometimes associated with tuberculosis in humans and other animals. These organisms are included in the “
M. tuberculosis
complex,” which includes
M. bovis, M. africanum,
and
M. microti,
as well as
M. tuberculosis. M. bovis
causes tuberculosis in cattle, humans and other primates, carnivores (e.g., dogs and cats), swine, parrots, and some birds of prey. Human disease is virtually indistinguishable from that caused by
M. tuberculosis,
and is treated in a similar manner (Nolte and Metchock, supra, at 402). Similarities between
M. bovis
and
M. tuberculosis
led to the development of the bacillus of Calmette-Guérin (BCG) an attenuated form of
M. bovis,
as a vaccine against tuberculosis in many parts of the world (See e.g., W. K. Joklik et al. (eds.),
Zinsser Microbiology,
18th ed., Appleton-Century Crofts, Norwalk, Conn., [1984], p. 564).The human health problems associated with
M. bovis
were largely responsible for the development of methods for the pasteurization of milk and the adoption of compulsory pasteurization in the early 1900s (See, C. O. Thoen, “Tuberculosis in wild and domestic mammals,” in B. R. Bloom (ed.)
Tuberculosis: Pathogenesis, Protection and Control,
American Society for Microbiology, Washington, D.C. [1994], pages 157-162).
M. africanum
has been reported from cases of tuberculosis in tropical Africa.
M. microti
causes generalized tuberculosis in voles, and produces local lesions in such animals as guinea pigs, rabbits, and calves (Nolte and Metchock, supra, at 402).
Thus,
M. tuberculosis
is not the only respiratory pathogen of great public health concern, and neither is the
M. tuberculosis
complex. Recent developments in the taxonomy and study of the mycobacteria have resulted in recognition of
M. avium
complex (MAC) organisms as the cause of disseminated disease in immunocompromised patients, in particular AIDS patients. The two major species associated with MAC are
M. avium
and
M. intracellulare.
However, the MAC includes
28
serovars of these two distinct species, although three additional serovars of
M. scrofulaceum
(i.e.,
M. avium—M. intracellulare—M. scrofulaceum
complex) were previously included. Within the
M. avium
species, three subspecies have been proposed, based on phenotypic and genotypic characteristics (
M. avium
subspecies
avium, M. avium
subspecies
paratuberculosis,
and
M. avium
subspecies
silvaticum
) (M.-F. Thorel et al., Numerical taxonomy of mycobactin-dependent mycobacteria, emended description of
Mycobacterium avium,
and description of
Mycobacterium avium
subsp.
avium,
subsp. nov.
M. avium
subsp.
Case Western Reserve University
Medlen & Carroll LLP
Swartz Rodney P
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