Table of Contents:

• Taxonomy Information
• Lifecycle Information
• Genome Information
• Biosafety Information
• Culturing Information
• Epidemiology Information
• Diagnostic Tests Information
• Infected Hosts Information
• Phinet: Pathogen-Host Interaction Network
• Lab Animal Pathobiology & Management
• References
• Data Provenance and Curators

1. Species:
   1. Mycobacteria tuberculosis (Website 1):
      1. Common Name: TB
      2. GenBank Taxonomy No.: 1773
      3. Description: The Mycobacterium tuberculosis belongs to the genus Mycobacterium, which are aerobic, nonmotile, and rod-shaped bacteria with two distinguishing characteristics: acid-fastness and slow growth(Grange, 1998a). Mycobacterium tuberculosis is one of most successful pathogens of mankind, infecting one-third of the global population and claiming two million lives every year. The ability of the bacteria to persist in the form of a long-term asymptomatic infection, referred to as latent tuberculosis, is central to the biology of the disease(Stewart et al., 2003). Approximately eight million people develop active tuberculosis (TB) every year, with two million dying from the disease. In addition to this already huge burden of disease, it is estimated that up to two billion people have been infected with the causative agent, Mycobacterium tuberculosis. Most people control the initial infection by mounting a cell-mediated immune response that prevents disease but can leave a residual population of viable mycobacteria. Between 5 - 10% of individuals who become infected subsequently develop clinical disease. Primary TB develops within 1 or 2 years after an initial infection and, particularly in children, is often associated with disseminated disease. Post-primary TB develops later in life, and can be caused either by reactivation of bacteria remaining from the initial infection or by failure to control a subsequent reinfection. Post-primary TB is predominantly a pulmonary disease, involving extensive damage to the lungs and efficient aerosol transmission of bacteria. The risk of disease is highly dependent on the immune status of the host; coinfection with HIV markedly increases the incidence of both forms of disease(Stewart et al., 2003).
      4. Variant(s):
         • Mycobacterium tuberculosis H37Rv (Website 2):
           • Common Name: TB H37RV
           • GenBank Taxonomy No.: 83332
           • Parents: Mycobacteria tuberculosis
           • Description: Mycobacterium tuberculosis H37Rv was first isolated in 1905, has remained pathogenic and is the most widely used strain in tuberculosis research(Camus et al., 2002).
         • Mycobacterium tuberculosis CDC1551 (Website 3):
           • Common Name: TB CDC1551
           • GenBank Taxonomy No.: 83331
           • Parents: Mycobacteria tuberculosis
           • Description: CDC 1551 is a recent clinical isolate which was responsible for an outbreak of TB in a rural area of the USA in 1995. Due to the high rate of skin-test conversion that occurred and the large skin-test response to purified protein derivative of tuberculin (PPD) of those infected, CDC 1551 was considered to be unusually infectious in man. In addition, evaluation of the growth of CDC 1551 in lungs of mice 20 d after aerosol infection gave 100-fold higher numbers of bacilli compared to the numbers of bacilli isolated from the lungs of mice infected with the M. tuberculosis laboratory strain Erdman. As a result of these findings, CDC 1551 was assumed to be highly virulent and was selected for sequencing by the National Institutes of Health(Betts et al., 2000).
         • Mycobacterium tuberculosis 210 (Website 4):
           • Common Name: TB 210
           • GenBank Taxonomy No.: 164513
           • Parents: Mycobacteria tuberculosis
           • Description: A widely distributed strain, designated 210. The strain was characterized by a 21-band fingerprint pattern when probed with IS6110. Currently, the 210 strain has been shown to account for 215 cases of tuberculosis in five states. To determine whether the dissemination of this strain correlated with its capacity for replication, the intracellular growth rate of strain 210 in human macrophages was measured. Compared to isolates from other clusters or from non-clustered patients, strain 210 grew significantly faster. The data indicate that the 210 strain should also be considered a W variant(Beggs et al., 2000).
         • Mycobacterium tuberculosis subsp. tuberculosis (Website 5):
           • Common Name: TB tb
           • GenBank Taxonomy No.: 182785
           • Parents: Mycobacteria tuberculosis
           • Description: The Mycobacterium tuberculosis complex consists of a highly related group of acid-alcohol-fast bacilli which are human and animal pathogens. It comprises five classical species. M. tuberculosis (sensu stricto) infects human and non-human primates. Several authors have stated that members of the complex should be grouped as varieties or subspecies of M. tuberculosis and that the division of the tuberculosis complex into five species is an artifact of the great historical interest in this pathogen. However, to our knowledge, the reclassification of these species as a single species has not been proposed formally. Their significance in human and veterinary medicine, and the differences in their epidemiology, pathology and antibiotic response mean that the former classification is a useful one(Aranaz et al., 1999).

1. 1. Stage Information:
      1. Bacilli:
         • Size: 0.3-0.6 to 1-4 um
         • Shape: Rods, straight or slightly curved, occurring singly or in occasional threads.
         • Picture(s):
           • Mycobacterium tuberculosis bacilli (Dennis Kunkel Microscopy, Inc.)
             
             
             
             Description: Dennis Kunkel file name:97229A(Dennis Kunkel Microscopy, Inc.).
         • Description: In natural circumstances, M. tuberculosis, the causative agent of TB, is transmitted by expulsion of nasal droplets from an infected human individual to an uninfected one. Nasal droplets, which contain tubercle bacilli and are no larger than 2 um in diameter, are able to penetrate to the alveoli of the respiratory tract of the uninfected individual. Alveolar macrophages, which sample the alveolar mucosa for foreign organisms, ingest the M. tuberculosis bacilli and enclose them in phagosomes. If these macrophages are activated, the mycobacteria containing phagosomes fuse with lysosomes, and the bacteria are killed. If, on the other hand, the alveolar macrophages are not activated, the bacilli survive and grow within the phagosomes by altering these intracellular compartments in some way to preclude normal maturation to phagolysosomes or to prevent fusions of the phagosomes to lysosomes. The bacilli multiply within the phagosomes until the macrophages lyse, probably because of bacillary burden, and the mycobacteria are released into the surrounding lung tissue, where they are phagocytized by tissue macrophages. Again, if the macrophages are activated, the bacteria are killed. However, if these tissue macrophages are not activated, the mycobacteria continue to multiply within the phagosomes and, upon release, are phagocytized by additional tissue macrophages(Clark-Curtiss and Haydel, 2003).

1. Genome of Mycobacteria tuberculosis
   1. Mycobacterium tuberculosis(Website 8)
      1. GenBank Accession Number: NC_000962,NC_002755
      2. Size: 4411532 bp(Camus et al., 2002). 4403837 bp(Website 6).
      3. Gene Count: 4056(Camus et al., 2002).
      4. Description: The original sequence and annotation of Mycobacterium tuberculosis strain H37Rv identified 3974 genes (Cole et al., 1998). This included 3924 genes thought to encode proteins and 50 encoding stable RNA. Following the re-annotation, we have included 82 additional genes. All of the new genes are believed to encode polypeptides and no change has been detected in the number of RNA molecules(Camus et al., 2002). The current nucleotide sequence now contains 4411532 nt(Camus et al., 2002).
      5. Picture(s):
         • H37Rv genome (Website 8)
           
           
           
           Description: H37Rv genome(Website 8).
         • CDC1551 genome (Website 7)
           
           
           
           Description: CDC1551 genome(Website 6).
         • H37Rv genome (Website 8)
           
           
           
           Description: H37Rv genome(Website 8).
         • CDC1551 genome (Website 7)
           
           
           
           Description: CDC1551 genome(Website 6).

1. Biosafety information for Mycobacteria tuberculosis
   1. Level: 2 and 3(CDC - Guidelines for safely working with M. tb).
   2. Precautions: Prevention of aerosols -- In most cases, the "laboratory accident" that results in an exposure and thus a tuberculin skin-test conversion is not as overt as the breakage of a bottle; more often, lapses in technique allow droplet nuclei to be released from culture-amplified materials. Therefore, all laboratory equipment and procedures should be evaluated when put into use and periodically thereafter to ensure that opportunities for generation of aerosols are minimized. Spill avoidance -- A spill can occur at any time during the processing of specimens. If a culture containing M. tuberculosis complex, whether in liquid or on solid medium, is dropped and broken, an aerosol is generated. Laboratory personnel should avoid practices that can result in spills (e.g., hand-carrying tubes, vials, and bottles, or improperly stacking racks or baskets). All tubes, plates, and other containers should be transported on carts in protected racks or baskets(CDC - Guidelines for safely working with M. tb).
   3. Disposal: When a spill occurs, all persons should leave the room immediately so that an assessment of the spill and exposure can be made without further personnel exposure. Two hours or more later, depending on the number of air changes in the laboratory, the degree of convectional mixing in the room air and the turbulence resulting from furniture and equipment placement, a person wearing a HEPA or N100 respirator (National Institute for Occupational Safety and Health, Occupational Safety and Health Administration) and protective clothing should reenter the room to cover the spill with towels soaked with a tuberculocidal disinfectant. After soaking for at least 2 hours, the spill should be cleaned up by a person wearing a respirator and protective clothing. When more intensive aerosolization of culture-amplified fluids occurs, the room should be sealed and decontaminated with formaldehyde gas(CDC - Guidelines for safely working with M. tb).

1. Solid Media (Woods, 2002):
   1. Description: Conventional culture of mycobacteria with solid media (egg-based, such as Lowenstein-Jensen or agar such as Middlebrook 7H11) requires incubation for 3 to 6 weeks and sometimes longer before there is sufficient growth for identification testing. Additionally, in most studies, solid media are less sensitive than liquid media for growth of mycobacteria, but neither type of medium recovers all isolates. Therefore, use of solid media alone for recovery of mycobacteria from clinical specimens not only delays diagnosis but also could potentially result in missed diagnoses. For these reasons, the 1993 CDC recommendations indicate that a broth system be used for primary mycobacterial culture and that a solid medium also be inoculated(Woods, 2002).
   2. Medium: Lowenstein-Jensen(American Thoracic Society, 2000). Middlebrook 7H10(American Thoracic Society, 2000). Middlebrook 7H11(American Thoracic Society, 2000).
   3. Optimal Temperature: 37C(Wayne et al., 1984).
   4. Lower Temperature: 30-34C(Wayne et al., 1984).
   5. Optimal pH: 6.8(Heifets and Sanchez , 2000).
   6. Upper pH: 7.0(Wayne et al., 1984).
   7. Lower pH: 6.4(Wayne et al., 1984).
   8. Doubling Time: 14-15 hours(Wayne et al., 1984).
   9. Picture(s):
      • Colonies of M. tuberculosis growing on media (Core Curriculum on Tuberculosis (2000))
        
        
        
        Description: Colonies of M. tuberculosis growing on media(Core Curriculum on Tuberculosis (2000)).
2. Liquid broth (Woods, 2002):
   1. Description: Broth-based culture systems typically user 7H-12 liquid medium and are much more rapid in providing results. When combined with DNA probes for rapid species identification, are capable of producing positive results in 2 weeks or less for the vast majority of sputum smear-positive specimens, and within 3 weeks for smear-negative specimens(Schluger et al., 2003).
   2. Medium: Middlebrook 7H12(Woods, 2002). Middlebrook 7H9(Woods, 2002). Kirchner(Woods, 2002).
3. BACTEC 460TB (Siddiqi et al., 1981):
   1. Description: For many years, the only culture system with the potential to meet the CDC target for growth and detection of mycobacteria was the semi-automated radiometric BACTEC 460 TB (BD Biosciences, Spars, MD), which not only decreases time to detection of growth but also increases rate of recovery, compared with solid media. This system, however , is labor-intensive, and because the broth medium contains C14, laboratories must comply with the various safety and regulatory issues associated with the use of radioisotopes. Additionally, cross-contamination of battles by the instrument is a potential problem(Woods, 2002).
   2. Medium: Middlebrook 7H12(Siddiqi et al., 1981).
   3. Optimal Temperature: 37C(Siddiqi et al., 1981).
   4. Upper Temperature: 38C(Siddiqi et al., 1981).
   5. Picture(s):
      • BD BACTEC 460TB Automated Mycobacterial Detection and Susceptibility Testing System (Becton, Dickinson and Company)
        
        
        
        Description: The BACTEC 460TB was the first automated system for mycobacteria testing. Today, the BACTEC 460TB System still serves as the benchmark of quality and reliability for laboratories that require detection, differentiation and susceptibility from a single instrument. Used with permission of Becton, Dickinson and Company(Becton, Dickinson and Company).
4. MB/BacT (Manterola et al., 1998):
   1. Description: The MB/BacT system (MB/BacT; Organon Teknika, USA) is a fully automated, rapid, nonradiometric system for the culture of mycobacteria from clinical specimens other than blood. The MB/BacT system employs a colorimetric sensor and reflected light to monitor the presence and production of carbon dioxide (CO2) dissolved in the culture medium. If mycobacteria are present in the test sample, CO2 is produced as the organisms metabolize the substrates in the culture medium. When growth of the microorganisms produces CO2, the color of the gas-permeable sensor at the bottom of each culture bottle changes from dark green to bright yellow. The lighter color results in an increase of reflectance units monitored by the system(Manterola et al., 1998).
   2. Medium: The MB/BacT system consists of a bottle containing basic broth (Middlebrook 7H9; Organon Teknika), casein, bovine serum albumin, and catalase. Bottles contain 10 ml of media and are prepared with an atmosphere of CO2 in oxygen under vacuum. They are designed for use with the MB/BacT antibiotic supplement (amphotericin B 0.018% w/v, azlocillin 0.0034% w/v, nalidixic acid 0.04% w/v, polymyxin B 10000 U, and trimethoprim 0.0105% w/v)(Manterola et al., 1998).
   3. Optimal Temperature: 37C(Manterola et al., 1998).
5. ESP II system (Woods et al., 1997):
   1. Description: The ESP Culture System II (ESP II; Difco Laboratories, Detroit, Mich.) is a fully automated, continuously monitoring system for growth and detection of microorganisms, including mycobacteria, that has recently received clearance by the Food and Drug Administration for mycobacterial culture. ESP II is an adaptation of the ESP blood culture system that has been available for clinical use for over 3 years. The technology is based on detection of pressure changes within the headspace above the broth culture medium in a sealed bottle, i.e., either gas production or gas consumption due to microbial growth. A special detection algorithm has been developed for the very slowly growing mycobacteria, in addition to the current ESP detection algorithm(Woods et al., 1997).
   2. Medium: Difco ESP II bottle, with antibiotic supplement (polymyxin B, vancomycin, nalidixicacid, and amphotericin B [PVNA]) and a growth supplement (Middlebrook OADC enrichment)(Woods et al., 1997).
   3. Optimal Temperature: 35C(Woods et al., 1997).
   4. Picture(s):
      • ESP Culture System II (TREK Diagnostic Systems)
        
        
        
        Description: ESP is the first fully automated culture system FDA-cleared for routine blood culture, mycobacteria detection, and M. tuberculosis susceptibility testing on a single instrument platform(TREK Diagnostic Systems).
6. BACTEC 9000MB (Zanetti et al., 1997):
   1. Description: A new, fully automated, nonradiometric method, fluorescent BACTEC 9000 MB (Becton Dickinson), which uses an oxygen-quenched fluorescence indicator for the rapid detection of Mycobacterium spp., has been introduced. The fluorescence of the sensor is a function of the oxygen depletion that results during microbial metabolism. The presence of fluorescence indicates growth of microorganisms(Zanetti et al., 1997).
   2. Medium: The medium used in BACTEC 9000 MB is a modified Middlebrook broth formulation (Myco/F sputa; Becton Dickinson Microbiology Systems, Sparks, Md.). Each Myco/F vial was supplemented with 2 ml of supplement F enrichment (lactic acid [3.5 mg/ml], polyoxyethylene stearate [2.3 mg/ml], bovine serum albumin [116.0 mg/ml], dextrose [23.0 mg/ml], biotin [0.012 mg/ml] [Becton Dickinson]) and with an antimicrobial mixture of PANTA (polymyxin B [1,000 U/ml], amphotericin B [100 mg/ml], nalidixic acid [400 mg/ml], trimethoprim [100 mg/ml], azlocillin [200 mg/ml] [Becton Dickinson])(Zanetti et al., 1997).
   3. Optimal Temperature: 37C(Zanetti et al., 1997).
   4. Picture(s):
      • BD BACTEC 9000MB Mycobacterial Detection System (Becton, Dickinson and Company)
        
        
        
        Description: The BACTEC 9000MB continuously monitors samples around the clock to detect positives as they occur. Used with permission of Becton, Dickinson and Company(Becton, Dickinson and Company).
7. BACTEC MGIT 960 (Hanna et al., 1999):
   1. Description: The BACTEC MGIT 960 system is a fully automated, high capacity, nonradiometric, noninvasive instrument which requires neither needles nor other sharp implements to simultaneously incubate and monitor 960 7-ml culture tubes. To monitor microbial growth, the BACTEC MGIT 960 uses the same oxygen-quenching fluorescent sensor technology as both the manual Mycobacteria Growth Indicator Tube (BBL MGIT) and the BACTEC 9000MB system, in conjunction with unique on-board algorithms to determine the positivity of the culture tubes(Hanna et al., 1999).
   2. Medium: Middlebrook 7H9 broth base, to which was added an enrichment supplement containing oleic acid, albumin, dextrose, and catalase (BBL MGIT OADC) and an antibiotic mixture of polymyxin B, amphotericin B, nalidixic acid, trimethoprim, and azlocillin (BBL MGIT PANTA)(Hanna et al., 1999).
   3. Optimal Temperature: 37C(Hanna et al., 1999).
   4. Picture(s):
      • BD BACTEC MGIT 960 System for Mycobacteria Testing (Becton, Dickinson and Company)
        
        
        
        Description: The BACTEC MGIT 960 System builds on the legacy of simplicity, efficiency, performance and safety of the BACTEC 460TB and 9000MB instruments. Used with permission of Becton, Dickinson and Company(Becton, Dickinson and Company).

1. Outbreak Locations:
   1. Tuberculosis in Africa has reached epidemic proportions, with an estimated 2 million new cases occurring annually, increasing at a rate of 10% each year, largely as a result of HIV co-infection. Consequently, the numbers of TB cases in Africa are projected to double in the next decade because of the HIV epidemic and under-funding of effective strategies against TB. TB is the world's leading killer among infectious diseases, with one person dying of it every 15 s across the globe. In Africa, it is responsible for 600 000 deaths each year, mainly occurring among the young and economically productive age group. The situation is compounded by the fact that on average, 30-40% of the TB cases in Africa are HIV positive, this figure reaching 70% in some countries. On a global level, 80% of the 8 million TB cases occurring annually are in only 22 countries. Of the 10 countries with the highest incidence, nine are in Africa. Africa bears the additional burden of high levels of poverty and some of the lowest health indicators in the world. Natural calamities and man-made conflicts have worsened the situation in many countries, resulting in a large number of displaced persons. In addition, the AIDS epidemic has caused a reversal of the gains in development and has resulted in a decline in life expectancy in many countries(Mwinga and Fourie, 2004).
   2. The incidence of tuberculosis (TB) in Latvia, as in the rest of the world, has followed the same increasing trend. From 1991 to 1998, the incidence of TB in Latvia increased, reaching a rate of 74 per 100,000 inhabitants. Since then, it has remained at about this level. At the same time, drug resistance among TB patients in Latvia seems to be the highest in the world, with primary multidrug resistance found in 8.6% of new cases and in 34.5% of all TB patients in the year 2000(Tracevska et al., 2002).
   3. Tuberculosis is an emerging problem in penitentiary systems all over the world. Russia is not an exception; it has an enormous prison system with nearly 1 million inmates (0.7% of the current population). The high number of imprisoned persons, overcrowded conditions, inadequate ventilation, and poor general health of inmates facilitate the spread of tuberculosis. In 2000, the incidence and mortality associated with tuberculosis in Russian prisons were 3174 cases and 171 deaths per 100,000 prisoners, respectively. The situation becomes worse if the disease is caused by drug-resistant Mycobacterium tuberculosis isolates. In prisons in some regions of Russia, the prevalence of resistance to 1 drug among new cases was 35% to 44%, and the prevalence of multidrug resistance (MDR; i.e., resistance to at least rifampin and isoniazid) among new cases varied from 15% to 22%(Toungoussova et al., 2003). In the Archangel prison, Russia, isolates recovered from 34.0% and 55.0% of prisoners with new and previously treated cases of tuberculosis, respectively, had MDR. Comparison of the situation with that in the community revealed that MDR among new cases was 2.5 times higher in the prison settings; the rates of MDR among previously treated cases in the prison (55.0%) and the community (60.0%) were similar. The high rate of MDR and the identical RFLP patterns, spoligotypes, and rpoB mutations among new cases indicate active transmission of isolates with MDR between prisoners(Toungoussova et al., 2003). Patients with infectious tuberculosis who are imprisoned and those who are released from prison before treatment completion may play an important role in the disease epidemiology. Close coordination of tuberculosis programs in the prison and the community is important(Toungoussova et al., 2003).
   4. Strains of the Beijing/W genotype family of Mycobacterium tuberculosis have caused large outbreaks of tuberculosis, sometimes involving multidrug resistance. This genetically highly conserved family of M. tuberculosis strains predominates in some geographic areas(Glynn et al., 2002). Beijing strains were most prevalent in Asia but were found worldwide. Associations with drug resistance varied: in New York, Cuba, Estonia, and Vietnam, Beijing strains were strongly associated with drug resistance, but elsewhere the association was weak or absent. Although few reports have measured trends in prevalence, the ubiquity of the Beijing strains and their frequent association with outbreaks and drug resistance underline their importance(Glynn et al., 2002).
   5. Trend analysis has also confirmed that MDR-TB is not a major problem in countries implementing tuberculosis control according to international guidelines for several years. Botswana, Chile, Cuba, the Czech Republic, and Uruguay have all showed very low prevalence of MDR-TB confirming that efficient tuberculosis control prevents the outset and spread of MDR-TB throughout the years. Likewise, in developed countries with long history of tuberculosis control such as Australia, Canada, Denmark, France, the Netherlands, the United States, and the United Kingdom trends suggest that MDR-TB is not a major public health issue but problem limited to specific groups including immigrants, refugees, and homeless(Espinal et al., 2003).
   6. This outbreak demonstrates that tuberculosis can spread in a neighborhood bar if one of the regular patrons is highly infectious. The index patient had a progressively worsening cough, and over a period of six months his weight declined from 80 to 49 kg. There was no intervention, however, even though he was eligible for health care under government programs. There was a public clinic within six blocks of the bar and a public hospital within three miles, yet he did not seek health care, nor did any of the bars employees or customers intervene. Instead, the patient went untreated until he could barely stand unassisted, had extensive destruction of lung tissue, and had infected numerous others. His alcoholism and mental health problems were a highly effective barrier to health care. Though it would have been difficult, early intervention would probably have reduced the extent of the outbreak. The index patient proved highly infectious. Forty-one of 97 contacts (42 percent) interviewed at the bar were infected. Active tuberculosis developed in 14 of 97 (14 percent). These numbers are higher than expected. In a typical contact investigation, approximately 20 to 30 percent of the close contacts have positive tuberculin skin tests and in only 1 or 2 percent does active tuberculosis develop. Also higher than expected was the proportion of the people we surveyed who were infected but without disease initially (i.e., they had positive tuberculin skin tests, normal chest films, and no symptoms), yet who later progressed to active disease. Nineteen such people were offered isoniazid prophylaxis. Six completed therapy and remained well, but 13 refused preventive therapy or were noncompliant. In 3 of these 13 (23 percent), active tuberculosis developed within two years. Typically, in approximately 5 percent of the people who convert to positive tuberculin skin tests, active tuberculosis develops in one year, and in an additional 5 percent it develops at some time during their lives(Kline et al., 1995).
   7. There is great potential for extensive transmission of TB in a high school setting by an adolescent index patient. Schools are the most common site reported for community-based outbreaks. Contributing factorsinclude delay in diagnosis, sustained contact, and inadequate ventilation or overcrowding(Phillips et al., 2004). In May 2001, a case of highly infectious TB was diagnosed in a 15-year-old high school student in rural Missouri(Phillips et al., 2004). The transmission of TB followed a predictable pattern at the high school. Students with the most exposure, those in <=3 classes with the patient, were most at risk (Relative Risk: 5.7)(Phillips et al., 2004). Of the 5 household contacts, all were infected and 3 (60%) had developed active TB disease. Of the 781 high school students sought for TB screening, 559 (72%) completed testing, and 58 (10%) were PPD-positive. Sixty-seven bus riders were sought for testing and 7 (19%) were purified protein derivative (PPD)-positive, with 1 bus rider subsequently diagnosed with active disease(Phillips et al., 2004).
   8. The Public Health Seattle and King County (PH-SKC) Tuberculosis Control Program, with assistance from the Washington State Department of Health and CDC, is continuing to investigate an ongoing outbreak(MMWR, 2003). As of September 30, 2003, PH-SKC had identified 44 outbreak-associated TB patients with dates of diagnosis during May 2002-September 2003(MMWR, 2003). All but three of the outbreak-associated patients were homeless at the time of diagnosis; 43 (98%) were born in the United States, 34 (77%) were male, 21 (48%) were American Indian/Alaska Native, and 17 (39%) were black. Of the 38 (86%) patients with pulmonary disease, 23 (61%) had acid-fast bacilli identified on sputum smear at diagnosis. Seven (16%) outbreak-associated patients also were infected with human immunodeficiency virus (HIV)(MMWR, 2003). Focused, intensified screening efforts for early detection and treatment of both TB disease and LTBI are under way to control transmission in the King County community. TB controllers, particularly those from western states, should consider the possibility of unrecognized TB outbreaks involving homeless persons in their communities(MMWR, 2003).
   9. The transient nature of a homeless persons life often interferes with the timely diagnosis and successful treatment of TB(McElroy et al., 2003). We describe an outbreak investigation of a cluster of TB cases at a large homeless shelter in Raleigh, North Carolina, and how the frequency of stays at the shelterincreased the risk of M. tuberculosis infection. Overcoming the challenge of finding additional undiagnosed cases and the many contacts in need of treatment for LTBI required novel approaches(McElroy et al., 2003). In addition to the initial index cluster of 9 patients, another 16 patients were identified. Isolates of M. tuberculosis from all 25 patients shared a matching DNA fingerprint pattern. All but 1 patient was male, 22 (88%) were African American, and 14 (56%) were human immunodeficiency virusinfected. An epidemiological link to a single shelter was identified for all but 1 patient. Earlier recognition of this shelter as a site of M. tuberculosis transmission could have been facilitated through innovative approaches to contact investigation and through genetic typing of isolates(McElroy et al., 2003).
   10. In January 2001, the US Centers for Disease Control and Prevention (CDC) assisted the Wichita-Sedgwick County Department of Health and the Kansas Department of Health and Environment in investigating a cluster of 22 TB patients diagnosed between 1994 and 2001. Patients included 10 men, nine women, and three children. Seven of the nine female patients had sputum acid-fast bacilli (AFB) smear-positive cavitary pulmonary TB at the time of diagnosis and worked as exotic dancers in the Wichita area. (Exotic dancers are usually women employed by clubs to dance nude or near-nude for the entertainment of men, although either sex can be the dancer or the observer.) All three pediatric patients had household contact with at least one exotic dancer with TB. Epidemiologic links to female patients had previously been established for the majority of male patients through routine contact investigation procedures(McElroy et al., 2003). In consultation with state and local health authorities, all adult outbreak-associated cases and selected named and unnamed contacts were reinterviewed using a network analysis questionnaire(McElroy et al., 2003). Network-based methods may provide evidence for direct connections among cases and persons with LTBI, as well as indirect evidence, such as overlap in attendance at places of social aggregation and drug using behaviors(McElroy et al., 2003). Network analysis can help discern behavior or relationship differences among various members of a seemingly similar group, and show the variation in behaviors that may explain transmission(McElroy et al., 2003).
   11. In May and June of 1994, four cases of TB caused by M. tuberculosis isolates resistant to isoniazid (H) and rifampin (R) were reported among clients of the same methadone treatment program (MTP). The MTP servers approximately 300 clients, and provides individual and group counseling, detoxification, and methadone maintenance services(Conover et al., 2001). Thirteen cases of MDR-TB were diagnosed among MTP clients during the outbreak period(Conover et al., 2001). Two cases were HIV negative and 11 were coinfected with HIV (median CD4 count 146 cells/ml |range 25-326|). All cases had isolates resistant to isoniazid and rifampin only, and 12 isolates available for RFLP analysis had matching4-band patterns by IS6110 typing and were also identical by pTBN12 typing. Overall mortality among cases during the outbreak period was 69.2% (9 / 13); five cases had received less than 2 weeks of treatment for MDR-TB at the time of death(Conover et al., 2001). Although some transmission of M. tuberculosis among MTP clients may have occurred outside the MTP, there is strong evidence that most transmission took place in the MTP setting. Evidence for transmission at the MTP includes conversions among staff without other known exposures during the outbreak period, no other identified site of exposure for sever cases despite extensive investigation, clustering of cases in a counseling group, and higher rates of skin test conversion during periods when an infectious case with sever cavitary disease was also in attendance(Conover et al., 2001).
   12. We recently investigated an outbreak of tuberculosis that affected four unrelated children who attended a family day care home (DCH). The source case was identified as the 40-year-old daughter of the DCH provider who assisted in the children's care. Our findings illustrate the significant risk of infection among children that can result from an unidentified case of active pulmonary tuberculosis in a DCH provider(Leggiadro et al., 1989).
   13. In March 1992, a 39-year-old HIV-infected male was admitted to San Mateo County General Hospital with a 3-month history of productive cough. Abundant acid-fast bacilli on initial sputum smears indicated pulmonary tuberculosis. Three days later, a 73-year-old male with tuberculosis, presenting with fevers and chills was admitted to the same hospital. The patient with the initial index case was a transient resident in two houses, in one of which the second person admitted also lived, in an economically depressed neighborhood known for its high crime rate and drug use. Public health workers discovered, on interview with the two affected individuals, that both houses provided lodging for several extended families with children and initiated an investigation(Leonhardt et al., 1994). Public health workers conducted interviews at the two residences in which the source patient resided and in the neighborhood. Children and adults indicated they lived in different residences in the neighborhood for various lengths of time, often with friends or relatives. Drug use, particularly use of crack cocaine, was disclosed by several individuals(Leonhardt et al., 1994). Fifty-seven percent (17 of 30) of the highly exposed contacts were 18 years of age or less(Leonhardt et al., 1994). Thirteen active cases (class III) were diagnosed, 11 involving children 18 years of age or less. Symptoms of active tuberculosis were present in four of the class III patients(Leonhardt et al., 1994).
2. Transmission Information:
   1. From: Humans, Homo sapiens (at lifecycle stage: Bacilli) , To: Humans, Homo sapiens (at lifecycle stage: Bacilli)
      Mechanism: Tuberculosis is spread from person to person through the air by droplet nuclei, particles 1 to 5 um in diameter that contain M. tuberculosis complex. Droplet nuclei are produced when persons with pulmonary or laryngeal tuberculosis cough, sneeze, speak, or sing. They also may be produced by aerosol treatments, sputum induction, aerosolization during bronchoscopy, and through manipulation of lesions or processing of tissue or secretions in the hospital or laboratory. Droplet nuclei, containing two to three M. tuberculosis organisms, are so small that air currents normally present in any indoor space can keep them airborne for long periods of time. Droplet nuclei are small enough to reach the alveoli within the lungs, where the organisms replicate(American Thoracic Society, 2000).
   2. From: Humans, Homo sapiens (at lifecycle stage: Bacilli) , To: Mammals (non-human), Callithrix jacchus (at lifecycle stage: Bacilli)
      Mechanism: We believe the direction of transmission in this case to have been from human to monkey (anthropozoonosis). The fact that the animal had lived in the owners household from a very young age minimizes the possibility of infection through other sources and thus the possibility of passing on the infection to the owner(Michel and Huchzermeyer, 1998). Genomic typing of M. tuberculosis by the RFLP method is a powerful tool in epidemiological studies to trace common sources of infection. In our investigation this genomic typing method was successfully used to demonstrate the identity of the 2 isolates and at the same time the zoonotic character of tuberculosis(Michel and Huchzermeyer, 1998).
   3. From: Humans, Homo sapiens (at lifecycle stage: Bacilli) , To: Birds, Ara chloropterus (at lifecycle stage: Bacilli)
      Mechanism: This report describes a macaw with active tuberculosis caused by M. tuberculosis. Epidemiologic investigation revealed that two people who lived in the same house with the pet bird and who had close respiratory contact with it had active tuberculosis 3 to 4 years before diagnosis of tuberculosis in the bird. One patient did not adhere to antituberculosis treatment for more than 1 year. The bird probably contracted the disease from its human housemates(Washko et al., 2002).
   4. From: Mammals (non-human), Elephas maximus (at lifecycle stage: Bacilli) , To: Humans, Homo sapiens (at lifecycle stage: Bacilli)
      Mechanism: This report describes the first case of zoonotic M. tuberculosis transmission(Michalak et al., 1998). The possible mechanisms of transmission include close contact while handling and training elephants, cleaning the barn, participating in elephant necropsies, and living in close proximity to the elephant barn(Michalak et al., 1998).
   5. From: Mammals (non-human), Saimiri sciureus (at lifecycle stage: Bacilli) , To: Mammals (non-human), Macaca mulatta (at lifecycle stage: Bacilli)
      Mechanism: Six weeks after the death of monkey 1, an adult female rhesus monkey in the room that formerly housed monkey 1 was coughing and had an abscess in the right inguinal region. It had been in the colony for 21 months, and had been tuberculin-test negative when tested at 6-month intervals(Leathers and Hamm, 1976). A strong circumstantial case exists for transmission of infective material from one of the infected monkeys to others in the same room(Leathers and Hamm, 1976).
3. Environmental Reservoir:
   1. Human population:
      1. Description: An estimated 2 billion people worldwide are infected with M. tuberculosis an enormous reservoir of potential tuberculosis cases(Tufariello et al., 2003).
4. Intentional Releases:
   1. Currently no intentional releases information is available.

1. Organism Detection Test:
   1. Acid Fast Bacilli (AFB) stain for light microscopy (Woods, 2002):
      1. Time to Perform: 1-hour-to-1-day
      2. Description: The first step in the diagnosis of mycobacterial infection is microscopic examination of a smear prepared from a concentrated specimen and stained for acid-fast bacilli (AFB)(Woods, 2002). The carbolfuchin stains (Ziehl-Neelsen and Kinyoun methods), viewed with a light microscope under oil immersion(Woods, 2002). AFB smear does not allow identification of the infecting mycobacterium to the species level(Woods, 2002).
      3. False Positive: 43%(American Thoracic Society, 1997).
      4. False Negative: 1%(American Thoracic Society, 1997).
      5. Picture(s):
         • TB on AFB smear (Core Curriculum on Tuberculosis (2000))
           
           
           
           Description: From CDC Online TB core curriculum course(Core Curriculum on Tuberculosis (2000)).
   2. Acid Fast Bacilli (AFB) stain for fluorescence microscopy (Woods, 2002):
      1. Time to Perform: 1-hour-to-1-day
      2. Description: The first step in the diagnosis of mycobacterial infection is microscopic examination of a smear prepared from a concentrated specimen and stained for acid-fast bacilli (AFB)(Woods, 2002). The stains most commonly used are the fluorochrome stains (auramine-rhodamine or auramine O), examined by fluorescence microscopy under lower magnifications (x150 and x450). Mycobacteria are most easily detected by fluorochrome stains, with which the bacilli fluoresce a bright yellow-green or range-yellow (depending on the stain) against a black background. Because of the increased sensitivity and shorter time required for screening, fluorochrome stains, recommended by the CDC, are preferred(Woods, 2002). AFB smear does not allow identification of the infecting mycobacterium to the species level(Woods, 2002).
2. Immunoassay Test:
   1. Tuberculin skin test (American Thoracic Society, 2000):
      1. Time to Perform: 1-to-2-days
      2. Description: The tuberculin skin test is currently the only widely used method for identifying infection with M. tuberculosis in persons who do not have tuberculosis disease. Although currently the tuberculin skin test antigens that are available are substantially less than 100% sensitive and specific for detection of infection with M. tuberculosis, no better diagnostic method is widely available. Proper use of the tuberculin skin test requires a knowledge of the antigen used (tuberculin), the immunologic basis for the reaction to this antigen, the technique(s) of administering and reading the test, and the results of epidemiologic and clinical experience with the test(American Thoracic Society, 2000). In the general U.S. population, the test's sensitivity is 0.59 to 1.0, the specificity is 0.95 to 1.0(Rose et al., 1995).
      3. False Positive: 0% - 5%(Rose et al., 1995).
      4. False Negative: 0% - 41%(Rose et al., 1995).
      5. Antigen:
         • Tuberculin
           • Antigen Source: Mycobacteria tuberculosis
      6. Antibody:
         • Many naturally produced by immune system
           • Antibody Source: Humans
           • Antibody GenBank Accession Number: NA (Find similar sequence in our pathogen protein library)
      7. Picture(s):
         • TST for TB - administer the TST (Core Curriculum on Tuberculosis (2000))
           
           
           
           Description: Administering the Tuberculin Skin Test: (1) Inject intradermally 0.1 ml of 5 TU PPD tuberculin. (2) Produce wheal 6 mm to 10 mm in diameter. (3) Do not recap, bend, or break needles, or remove needles from syringes. Follow universal precautions for infection control(Core Curriculum on Tuberculosis (2000)).
         • TST for TB - Interpret the TST (Core Curriculum on Tuberculosis (2000))
           
           
           
           Description: Administering the Tuberculin Skin Test: (1) Inject intradermally 0.1 ml of 5 TU PPD tuberculin. (2) Produce wheal 6 mm to 10 mm in diameter. (3) Do not recap, bend, or break needles, or remove needles from syringes. Follow universal precautions for infection control(Core Curriculum on Tuberculosis (2000)).
   2. QuantiFERON (CDC - Guidelines for safely working with M. tb):
      1. Time to Perform: 1-to-2-days
      2. Description: In 2001, the QuantiFERON-TB test (QFT) (manufactured by Cellestis Limited, Carnegie, Victoria, Australia) was approved by the Food and Drug Administration (FDA) as an aid for detecting latent Mycobacterium tuberculosis infection. This test is an in vitro diagnostic aid that measures a component of cell-mediated immune reactivity to M. tuberculosis. The test is based on the quantification of interferon-gamma (IFN-) released from sensitized lymphocytes in whole blood incubated overnight with purified protein derivative (PPD) from M. tuberculosis and control antigens(CDC - Guidelines for safely working with M. tb). Evaluation of diagnostic tests for LTBI in humans is hampered by the lack of a "gold standard." As a result, new tests are commonly compared with the TST, despite its well-documented limitations. Owing to the lack of a definitive standard, the IFN- assay was evaluated on the basis of its agreement with the TST in persons with varying degrees of risk for M. tuberculosis infection and in persons with documented and suspected active TB. Overall agreement between the TST and IFN- assay was good (83.1%, K= 0.60) as was agreement when the analysis was limited to persons for whom the test is intended, those subjects being screened for LTBI, groups 1 and 2 combined (84.7%, K= 0.55). Test concordance was 65% for persons with a positive TST and 90% for those with a negative TST(Mazurek et al., 2001).
      3. False Positive: Compared to TST: 10%(Mazurek et al., 2001).
      4. False Negative: Compared to TST: 32%(Mazurek et al., 2001).
      5. Antigen:
         • PPD from M. tuberculosis (tuberculin)
           • Antigen Source: Mycobacteria tuberculosis
         • PPD from Mycobacterium avium
           • Antigen Source: Mycobacteria tuberculosis
         • Phytohemaglutinin
           • Antigen Source: Humans
           • Antigen GenBank Accession Number: AAN78483 (Find similar sequence in our pathogen protein library)
         • Saline
           • Antigen Source: Mycobacteria tuberculosis
           • Antigen GenBank Accession Number: PPD from Mycobacterium avium (Find similar sequence in our pathogen protein library)
3. Nucleic Acid Detection Test:
4. Other Test:
   1. Drug Susceptibility by BACTEC systems :
      1. Time to Perform: more-than-7-days
      2. Description: Susceptibility testing is one of the 10 essential practice recommendations and performance indicators for management of TB. In 1993, CDC experts recommended that susceptibility testing be performed on the first isolate of M. tuberculosis obtained from each patient and that testing be repeated if the patient remained culture-positive after 3 months of receiving adequate therapy or if the patient did not respond clinically to therapy. They also proposed that susceptibility test results for the primary antituberculous drugs be reported within an average of 28 days of receipt of the specimen in the laboratory(Woods, 2002). Of the two systems (that have been cleared by the FDA for susceptibility testing of the MTBC), only the BACTEC 460 TB is approved for testing pyrazinamide(Woods, 2002). The performance of BACTEC MGIT 960 was found similar to that of BACTEC 460 TB and this new system can be considered a good alternative to the radiometric method for routine susceptibility testing of M. tuberculosis(Ardito et al., 2001).
   2. RFLP of IS6110 for strain typing :
      1. Time to Perform: more-than-7-days
      2. Description: The insertion sequence IS6110 is present in different copy numbers (between 0 and 25 copies) in the M. tuberculosis complex and is integrated at various chromosomal sites. Restriction fragments based upon the IS6110 element are highly polymorphic but stable enough for epidemiologic investigations. Several molecular biological techniques have been developed based on IS6110 polymorphism(Mostrom et al., 2002). For the past decade, this method has been the reference standard for strain identification of M. tuberculosis owing to its high discriminatory index and its reproducibility. It is often used for verification of results produced by newer, more rapid, PCR-based methods(Mostrom et al., 2002).
      3. Picture(s):
         • IS6110 RFLP Fingerprints of M. tuberculosis (CDC TB / Mycobacteriology Research Laboratory)
           
           
           
           Description: IS6110 Fingerprints of M. tuberculosis, This autoradiograph is referred to as a fingerprint(CDC TB / Mycobacteriology Research Laboratory).
   3. Spoligotyping for strain typing :
      1. Time to Perform: 1-to-2-days
      2. Description: Groenen et al. initially studied a polymorphic preferential locus for the IS6110 element, referred to as the DR region, and proposed that this region should be used for epidemiological studies of the M. tuberculosis complex. Later, Kamerbeek et al. presented a rapid method for analyzing this region, referred to as spoligotyping. This method is today, next to IS6110-RFLP, the most widespread method for tuberculosis epidemiology(Mostrom et al., 2002). Spoligotyping is very widely-used, due to its simplicity, its high reproducibility, and its binary result format; and advantage when using databases. Unfortunately spoligotypings low-to-medium discriminatory capacity, depending on the geographic setting studied, makes it necessary to use a second method to underline potential epidemiological clusters. Comparison of local results to a worldwide spoligotyping database may provide information on the population genetics of the tubercle bacilli in a given setting(Mostrom et al., 2002).
   4. MIRU typing :
      1. Time to Perform: 1-to-2-days
      2. Description: Methods based on minisatellites that contain variable numbers of tandem repeats (VNTRs) have been demonstrated to be effective and portable methods for typing M. tuberculosis. Supply et al. have identified 41 such loci in the M. tuberculosis genome and termed them mycobacterial interspersed repetitive units (MIRUs). Twelve loci were demonstrated to vary in tandem repeat numbers and, in most, sequence between repeat units. These loci have formed the basis of a PCR-based typing method that has discrimination similar to that of high IS6110 copy number strains and better for low copy number strains. This method can be automated for large-scale typing projects using high throughput sequencing apparatus. It is reproducible, sensitive and specific for M. tuberculosis complex isolates(Kanduma et al., 2003).
   5. Gas chromotography / mass spectrometry (American Thoracic Society, 1997):
      1. Time to Perform: 1-hour-to-1-day
      2. Description: Tuberculostearic acid is a fatty acid present only in mycobacteria. It can be detected with gas chromatography/mass spectrometry in clinical samples containing small numbers of mycobacteria. Its detection provides a diagnostic test of high sensitivity and very high specificity, as illustrated in Table V. Because of the complexity and equipment requirements of the assay, it is unlikely to become widely available and is unlikely to be used in developing countries. However, it is available at the Centers for Disease Control in Atlanta, Ga. At the present time the detection of the tuberculostearic acid in cerebrospinal fluid probably represents the best approach to the rapid diagnosis of tuberculous meningitis. Since this form of tuberculosis is difficult to diagnose by standard clinical and microbiologic techniques, the detection of tuberculostearic acid is an important addition to the roster of tests for the rapid diagnosis of tuberculosis(American Thoracic Society, 1997).
      3. False Positive: Sputum: 0.5%(French et al., 1987b). Cerebrospinal fluid: 0.5%(French et al., 1987a).
      4. False Negative: Sputum: 2.9(French et al., 1987b). Cerebrospinal fluid: 4.5%(French et al., 1987a).

1. Humans
   1. Taxonomy Information:
      1. Species:
         1. Homo sapiens (Website 10):
            • Common Name: Homo sapiens
            • GenBank Taxonomy No.: 9606
            • Description: M. tuberculosis causes tuberculosis (TB), one of the oldest known human infectious diseases, and this bacterium is estimated to infect one-third of the global population(Monack et al., 2004).
   2. Infection Process:
      1. Infectious Dose: Very low, 1-5 tubercle bacilli(Balasubramanian et al., 1994),
      2. Description: Tuberculosis is spread from person to person through the air by droplet nuclei, particles 1 to 5 um in diameter that contain M. tuberculosis complex. Droplet nuclei are produced when persons with pulmonary or laryngeal tuberculosis cough, sneeze, speak, or sing. They also may be produced by aerosol treatments, sputum induction, aerosolization during bronchoscopy, and through manipulation of lesions or processing of tissue or secretions in the hospital or laboratory. Droplet nuclei, containing two to three M. tuberculosis organisms, are so small that air currents normally present in any indoor space can keep them airborne for long periods of time. Droplet nuclei are small enough to reach the alveoli within the lungs, where the organisms replicate(American Thoracic Society, 2000),
      3. Picture(s):
         • Aerosol transmission of Tuberculosis (Core Curriculum on Tuberculosis (2000))
           
           
           
           Description: Tuberculosis is spread by droplet nuclei which are expelled when a person with infectious TB coughs, sneezes, speaks, or sings(Core Curriculum on Tuberculosis (2000)).
   3. Disease Information:
      1. Tuberculosis(i.e., Active Tuberculosis) :
         1. Incubation: Although the risk of development of active disease varies according to time since infection, age, and host immunity, the estimated lifetime risk of disease for a newly infected young child is 10%, with roughly half of that risk occurring in the first 2 years after infection(Frieden et al., 2003), Of 100,00 persons aged 20 to 34 with a positive tuberculin test and without other risk factors for tuberculosis, we estimate that 918 cases of nonfatal tuberculosis would occur over a 20-year period(Taylor et al., 1981), We used the value of 47 cases annually per 100,000 reactors; this value is the mean of the higher (65 cases per 100,000) and lower (28 cases per 100,000) rates reported(Taylor et al., 1981),
         2. Prognosis:
            Globally, of the 1.23 million cases of tuberculosis registered by the WHO in 2000, 69.8% were cured, 9.6% completed treatment with no laboratory confirmation of cure, 4.2% died, and 16.4% did not complete treatment or were lost to followup(World Health Organization, 2003), Just over one million new sputum smear-positive cases were notified under DOTS in 2000, approximately the same number that was registered for treatment in 2000. Of the registered DOTS cases, 98% were evaluated for treatment outcome. Seventy-four percent of the registered cases were cured and a further 8% completed treatment (no laboratory confirmation of cure), giving an overall treatment success rate of 82% in DOTS areas(World Health Organization, 2003),
         3. Diagnosis Summary: Criteria for the diagnosis of active tuberculosis vary according to the setting. Patients with persistent cough (eg, lasting longer than 2 weeks) should be assessed for tuberculosis. Other common symptoms include fever, night sweats, weight loss, shortness of breath, haemoptysis, and chest pain. Among children, important diagnostic clues are a history of previous exposure to an individual with tuberculosis or evidence of tuberculosis infection (eg, a positive tuberculin skin test). To improve the diagnostic yield in children, diagnostic algorithms and point scoring systems are often used, particularly in less developed countries. Tests for the diagnosis of tuberculosis vary in sensitivity, specificity, speed, and cost. Even if additional tests are done, however, culture is required for definite diagnosis and is essential for drug-susceptibility testing. The sputum smear is an inexpensive test that can be carried out rapidly; fluorochrome, Ziehl-Neelsen, and Kinyoun staining methods can be used. The International Union Against Tuberculosis and Lung Disease (IUATLD) and WHO recommend the Ziehl-Neelsen method under most circumstances(Frieden et al., 2003),
         4. Symptom Information :
            • Description: Tuberculosis involving any site may produce symptoms and findings that are not specifically related to the organ or tissue involved but, rather, are systemic in nature. Of the systemic effects, fever is the most easily quantified. The frequency with which fever has been observed in patients with tuberculosis varies from approximately 37 to 80% (33, 34). In one study (33), 21% of patients had no fever at any point in the course of hospitalization for tuberculosis. Of the febrile patients, 34% were afebrile within 1 wk, and 64% in 2 wk, of beginning treatment. The median duration of fever after beginning treatment was 10 d, with a range of 1 to 109 d. Loss of appetite, weight loss, weakness, night sweats, and malaise are also common but are more difficult to quantify and may relate to coexisting diseases(American Thoracic Society, 2000).
            • Syndrome -- Pulmonary tuberculosis :
              • Description: The most common clinical manifestation of tuberculosis is pulmonary disease(Frieden et al., 2003).
              • Observed:
                80%(Frieden et al., 2003),
              • Symptom -- Cough (American Thoracic Society, 2000):
                • Description: Cough is the most common symptom of pulmonary tuberculosis. Early in the course of the illness it may be nonproductive, but subsequently, as inflammation and tissue necrosis ensue, sputum is usually produced and is key to most of our diagnostic methods(American Thoracic Society, 2000).
              • Symptom -- Hemoptysis (American Thoracic Society, 2000):
                • Description: Hemoptysis may rarely be a presenting symptom but usually is the result of previous disease and does not necessarily indicate active tuberculosis. Hemoptysis may result from residual tuberculous bronchiectasis, rupture of a dilated vessel in the wall of a cavity (Rasmussens aneurysm), bacterial or fungal infection (especially Aspergillus in the form of a mycetoma) in a residual cavity, or from erosion of calcified lesions into the lumen of an airway (broncholithiasis)(American Thoracic Society, 2000).
              • Symptom -- Pleuritic pain (American Thoracic Society, 2000):
                • Description: Inflammation of the lung parenchymaadjacent to a pleural surface may cause pleuritic pain(American Thoracic Society, 2000).
              • Symptom -- Dyspnea (American Thoracic Society, 2000):
                • Description: Dyspnea is unusual unless there is extensive disease(American Thoracic Society, 2000).
              • Symptom -- Respiratory failure (American Thoracic Society, 2000):
                • Description: Tuberculosis may, however, cause severe respiratory failure(American Thoracic Society, 2000).
            • Syndrome -- Disseminated tuberculosis (American Thoracic Society, 2000):
              • Description: Disseminated tuberculosis occurs because of the inadequacy of host defenses in containing tuberculous infection. This failure of containment may occur in either latent or recently acquired tuberculous infection. Because of HIV or other causes of immunosuppression, the organism proliferates and disseminates throughout the body. Multiorgan involvement is probably much more common than is recognized because, generally, once M. tuberculosis is identified in any specimen, other sites are not evaluated. The term miliary is derived from the visual similarity of some disseminated lesions to millet seeds. Grossly, these lesions are 1- to 2-mm yellowish nodules that, histologically, are granulomas. Thus disseminated tuberculosis is sometimes called miliary tuberculosis. When these small nodules occur in the lung, the resulting radiographic pattern is also termed miliary(American Thoracic Society, 2000).
              • Symptom -- Non-specific (American Thoracic Society, 2000):
                • Description: Because of the multisystem involvement in disseminated tuberculosis, the clinical manifestations are protean(American Thoracic Society, 2000).
              • Symptom -- Choroidal tubercle (American Thoracic Society, 2000):
                • Description: A finding that is strongly suggestive of disseminated tuberculosis is the choroidal tubercle, a granuloma located in the choroid of the retina(American Thoracic Society, 2000).
                • Observed:
                  One study reported only 3 cases of iritis among 1073 cases of pts with systemic TB. Another series reported no cases of iritis in a series of 1000 pts with pulmonary TB. Donahue, in the 1960's, did a review of 10,535 patients being treated at TB sanatoriums, and only found 28 cases of iritis(Immunology Service of the Massachusetts Eye & Ear Infirmary),
              • Symptom -- Fever (American Thoracic Society, 2000):
                • Description: The presenting symptoms and signs are generally nonspecific and are dominated by systemic effects, particularly fever, weight loss, night sweats, anorexia, and weakness(American Thoracic Society, 2000).
              • Symptom -- Weight loss (American Thoracic Society, 2000):
                • Description: The presenting symptoms and signs are generally nonspecific and are dominated by systemic effects, particularly fever, weight loss, night sweats, anorexia, and weakness(American Thoracic Society, 2000).
              • Symptom -- Night sweats (American Thoracic Society, 2000):
                • Description: The presenting symptoms and signs are generally nonspecific and are dominated by systemic effects, particularly fever, weight loss, night sweats, anorexia, and weakness(American Thoracic Society, 2000).
              • Symptom -- Anorexia (American Thoracic Society, 2000):
                • Description: The presenting symptoms and signs are generally nonspecific and are dominated by systemic effects, particularly fever, weight loss, night sweats, anorexia, and weakness(American Thoracic Society, 2000).
              • Symptom -- Weakness (Asthenia) (American Thoracic Society, 2000):
                • Description: The presenting symptoms and signs are generally nonspecific and are dominated by systemic effects, particularly fever, weight loss, night sweats, anorexia, and weakness(American Thoracic Society, 2000).
              • Symptom -- Cough (American Thoracic Society, 2000):
                • Description: A productive cough is common because most patients with disseminated disease also have pulmonary involvement(American Thoracic Society, 2000).
              • Symptom -- Headache (American Thoracic Society, 2000):
                • Description: Headache and mental status changes are less frequent and are usually associated with meningeal involvement(American Thoracic Society, 2000).
              • Symptom -- Wasting (American Thoracic Society, 2000):
                • Description: Physical findings likewise are variable. Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy, and splenomegaly occur in descending order of frequency(American Thoracic Society, 2000).
              • Symptom -- Hepatomegaly (American Thoracic Society, 2000):
                • Description: Physical findings likewise are variable. Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy, and splenomegaly occur in descending order of frequency(American Thoracic Society, 2000).
              • Symptom -- Pulmonary findings (American Thoracic Society, 2000):
                • Description: Physical findings likewise are variable. Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy, and splenomegaly occur in descending order of frequency(American Thoracic Society, 2000).
              • Symptom -- Lymphadenopathy (American Thoracic Society, 2000):
                • Description: Physical findings likewise are variable. Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy, and splenomegaly occur in descending order of frequency(American Thoracic Society, 2000).
              • Symptom -- Splenomegaly (American Thoracic Society, 2000):
                • Description: Physical findings likewise are variable. Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy, and splenomegaly occur in descending order of frequency(American Thoracic Society, 2000).
            • Syndrome -- Lymph node tuberculosis :
              • Description: Tuberculous lymphadenitis usually presents as painless swelling of one or more lymph nodes. The nodes involved most commonly are those of the posterior or anterior cervical chain or those in the supraclavicular fossa. Frequently the process is bilateral and other noncontiguous groups of nodes can be involved. At least initially the nodes are discrete and the overlying skin is normal. With continuing disease the nodes may become matted and the overlying skin inflamed. Rupture of the node can result in formation of a sinus tract, which may be slow to heal. Intrathoracic adenopathy may compress bronchi, causing atelectasis leading to lung infection and perhaps bronchiectasis(American Thoracic Society, 2000).
              • Observed:
                The frequency of pulmonary involvement in reported series of patients with tuberculous lymphadenitis is quite variable, ranging from approximately 5 to 70%(American Thoracic Society, 2000),
              • Symptom -- Inflamation of skin :
                • Description: With continuing disease the nodes may become matted and the overlying skin inflamed.
              • Symptom -- Sinus tract (American Thoracic Society, 2000):
                • Description: Rupture of the node can result in formation of a sinus tract, which may be slow to heal(American Thoracic Society, 2000).
              • Symptom -- Atelectasis (American Thoracic Society, 2000):
                • Description: Intrathoracic adenopathy may compress bronchi, causing atelectasis leading to lung infection and perhaps bronchiectasis(American Thoracic Society, 2000).
              • Symptom -- Bronchiectasis (American Thoracic Society, 2000):
                • Description: Intrathoracic adenopathy may compress bronchi, causing atelectasis leading to lung infection and perhaps bronchiectasis(American Thoracic Society, 2000).
            • Syndrome -- Pleural tuberculosis (American Thoracic Society, 2000):
              • Description: There are two mechanisms by whichthe pleural space becomes involved in tuberculosis(American Thoracic Society, 2000). Early in thecourse of a tuberculous infection a few organisms may gain access to the pleural space and, in the presence of cell-mediatedimmunity, cause a hypersensitivity response. Commonly, this form of tuberculous pleuritis goes unnoticed, and the process resolves spontaneously. In some patients, however, tuberculous involvement of the pleura is manifested as an acute illness with fever and pleuritic pain. If the effusion is large enough, dyspnea may occur, although the effusions generally are small and rarely are bilateral(American Thoracic Society, 2000). The second variety of tuberculous involvement of thepleura is empyema. This is much less common than tuberculous pleurisy with effusion and results from a large number of organisms spilling into the pleural space, usually from rupture of a cavity or an adjacent parenchymal focus via a bronchopleural fistula. A tuberculous empyema is usually associated with evident pulmonary parenchymal disease on chest films and air may be seen in the pleural space. In the absence of concurrent pulmonary tuberculosis, diagnosis of pleural tuberculosis requires thoracentesis and, usually, pleural biopsy(American Thoracic Society, 2000).
              • Symptom -- Fever (American Thoracic Society, 2000):
                • Description: In some patients, however, tuberculous involvement of the pleura is manifested as an acute illness with fever and pleuritic pain(American Thoracic Society, 2000).
              • Symptom -- Pleuritic pain (American Thoracic Society, 2000):
                • Description: In some patients, however, tuberculous involvement of the pleura is manifested as an acute illness with fever and pleuritic pain(American Thoracic Society, 2000).
              • Symptom -- Dyspnea (American Thoracic Society, 2000):
                • Description: If the effusion is large enough, dyspnea may occur, although the effusions generally are small and rarely are bilateral(American Thoracic Society, 2000).
              • Symptom -- Empyema (American Thoracic Society, 2000):
                • Description: A tuberculous empyema is usually associated with evident pulmonary parenchymal disease on chest films and air may be seen in the pleural space(American Thoracic Society, 2000).
            • Syndrome -- Genitourinary tuberculosis (American Thoracic Society, 2000):
              • Description: In patients with genitourinary tuberculosis, local symptoms predominate and systemic symptoms are less common. Dysuria, hematuria, and frequent urination are common, and flank pain may also be noted. However, the symptoms may be subtle, and, often, there is advanced destruction of the kidneys by the time a diagnosis is established. In women genital involvement is more common without renal tuberculosis than in men and may cause pelvic pain, menstrual irregularities, and infertility as presenting complaints. In men a painless or only slightly painful scrotal mass is probably the most common presenting symptom of genital involvement, but symptoms of prostatitis, orchitis, or epididymitis may also occur(American Thoracic Society, 2000).
              • Symptom -- Dysuria (American Thoracic Society, 2000):
                • Description: A tuberculous empyema is usually associated with evident pulmonary parenchymal disease on chest films and air may be seen in the pleural space(American Thoracic Society, 2000).
              • Symptom -- Hematuria (American Thoracic Society, 2000):
                • Description: Dysuria, hematuria, and frequent urination are common, and flank pain may also be noted(American Thoracic Society, 2000).
              • Symptom -- Frequent urination (American Thoracic Society, 2000):
                • Description: Dysuria, hematuria, and frequent urination are common, and flank pain may also be noted(American Thoracic Society, 2000).
              • Symptom -- Flank pain (American Thoracic Society, 2000):
                • Description: Dysuria, hematuria, and frequent urination are common, and flank pain may also be noted(American Thoracic Society, 2000).
              • Symptom -- Renal destruction (American Thoracic Society, 2000):
                • Description: The symptoms may be subtle, and, often, there is advanced destruction of the kidneys by the time a diagnosis is established(American Thoracic Society, 2000).
              • Symptom -- Pelvic pain (American Thoracic Society, 2000):
                • Description: In women genital involvement is more common without renal tuberculosis than in men and may cause pelvic pain, menstrual irregularities, and infertility as presenting complaints(American Thoracic Society, 2000).
              • Symptom -- Menstrual irregularities (American Thoracic Society, 2000):
                • Description: In women genital involvement is more common without renal tuberculosis than in men and may cause pelvic pain, menstrual irregularities, and infertility as presenting complaints(American Thoracic Society, 2000).
              • Symptom -- Infertility (American Thoracic Society, 2000):
                • Description: In women genital involvement is more common without renal tuberculosis than in men and may cause pelvic pain, menstrual irregularities, and infertility as presenting complaints(American Thoracic Society, 2000).
              • Symptom -- Scrotal mass (American Thoracic Society, 2000):
                • Description: In men a painless or only slightly painful scrotal mass is probably the most common presenting symptom of genital involvement, but symptoms of prostatitis, orchitis, or epididymitis may also occur(American Thoracic Society, 2000).
              • Symptom -- Prostatitis (American Thoracic Society, 2000):
                • Description: In men a painless or only slightly painful scrotal mass is probably the most common presenting symptom of genital involvement, but symptoms of prostatitis, orchitis, or epididymitis may also occur(American Thoracic Society, 2000).
              • Symptom -- Orchitis (American Thoracic Society, 2000):
                • Description: In men a painless or only slightly painful scrotal mass is probably the most common presenting symptom of genital involvement, but symptoms of prostatitis, orchitis, or epididymitis may also occur(American Thoracic Society, 2000).
              • Symptom -- Epididymitis (American Thoracic Society, 2000):
                • Description: In men a painless or only slightly painful scrotal mass is probably the most common presenting symptom of genital involvement, but symptoms of prostatitis, orchitis, or epididymitis may also occur(American Thoracic Society, 2000).
            • Syndrome -- Skeletal tuberculosis :
              • Description: The usual presenting symptom of skeletal tuberculosis is pain. Swelling of the involved joint may be noted, as may limitation of motion and, occasionally, sinus tracts. Systemic symptoms of infection are not common. Since the epiphyseal region of bones is highly vascularized in infants and young children, bone involvement with tuberculosis is much more common in children than adults. Approximately 1% of young children with tuberculosis disease will develop a bony focus. Because of the subtle nature of the symptoms, diagnostic evaluations often are not undertaken until the process is advanced. Delay in diagnosis can be especially catastrophic in vertebral tuberculosis, where compression of the spinal cord may cause severe and irreversible neurologic sequelae, including paraplegia(American Thoracic Society, 2000).
              • Observed:
                Approximately 1% of young children with tuberculosis disease will develop a bony focus(American Thoracic Society, 2000),
              • Symptom -- Pain (American Thoracic Society, 2000):
                • Description: The usual presenting symptom of skeletal tuberculosis is pain. Swelling of the involved joint may be noted, as may limitation of motion and, occasionally, sinus tracts(American Thoracic Society, 2000).
              • Symptom -- Joint swelling (American Thoracic Society, 2000):
                • Description: Swelling of the involved joint may be noted, as may limitation of motion and, occasionally, sinus tracts(American Thoracic Society, 2000).
              • Symptom -- Limited motion (American Thoracic Society, 2000):
                • Description: Swelling of the involved joint may be noted, as may limitation of motion and, occasionally, sinus tracts(American Thoracic Society, 2000).
              • Symptom -- Sinus tracts (American Thoracic Society, 2000):
                • Description: Swelling of the involved joint may be noted, as may limitation of motion and, occasionally, sinus tracts(American Thoracic Society, 2000).
            • Syndrome -- Central nervous system tuberculosis :
              • Description: Tuberculous meningitis is a particularly devastating disease. Meningitis can result from direct meningeal seeding and proliferation during a tuberculous bacillemia either at the time of initial infection or at the time of breakdown of an old pulmonary focus, or can result from breakdown of an old parameningeal focus with rupture into the subarachnoid space. The consequences of subarachnoid space contamination can be diffuse meningitis or localized arteritis. In tuberculous meningitis the process is located primarily at the base of the brain(American Thoracic Society, 2000). The other major central nervous system form of tuberculosis, the tuberculoma, presents a more subtle clinical picture than tuberculous meningitis. The usual presentation is that of a slowly growing focal lesion, although a few patients have increased intracranial pressure and no focal findings. The cerebrospinal fluid is usually normal, and the diagnosis is established by computed tomographic or magnetic resonance scanning and subsequent resection, biopsy, or aspiration of any ring-enhancing lesion(American Thoracic Society, 2000).
              • Symptom -- Diffuse meningitis (American Thoracic Society, 2000):
                • Description: The consequences of subarachnoid space contamination can be diffuse meningitis or localized arteritis(American Thoracic Society, 2000).
              • Symptom -- Arteritis (American Thoracic Society, 2000):
                • Description: The consequences of subarachnoid space contamination can be diffuse meningitis or localized arteritis(American Thoracic Society, 2000).
              • Symptom -- Headache (American Thoracic Society, 2000):
                • Description: Symptoms, therefore, include those related to cranial nerve involvement as well as headache, decreased level of consciousness, and neck stiffness(American Thoracic Society, 2000).
              • Symptom -- Decreased consciousness (American Thoracic Society, 2000):
                • Description: Symptoms, therefore, include those related to cranial nerve involvement as well as headache, decreased level of consciousness, and neck stiffness(American Thoracic Society, 2000).
              • Symptom -- Neck stiffness (American Thoracic Society, 2000):
                • Description: Symptoms, therefore, include those related to cranial nerve involvement as well as headache, decreased level of consciousness, and neck stiffness(American Thoracic Society, 2000).
            • Syndrome -- Abdominal tuberculosis (American Thoracic Society, 2000):
              • Description: Tuberculosis can involve any intraabdominal organ as well as the peritoneum, and the clinical manifestations depend on the areas of involvement. In the gut itself tuberculosis may occur in any location from the mouth to the anus, although lesions proximal to the terminal ileum are unusual. The most common sites of involvement are the terminal ileum and cecum, with other portions of the colon and the rectum involved less frequently. In the terminal ileum or cecum the most common manifestations are pain, which may be misdiagnosed as appendicitis, and intestinal obstruction. A palpable mass may be noted that, together with the appearance of the abnormality on barium enema or small bowel films, can easily be mistaken for a carcinoma. Rectal lesions usually present as anal fissures, fistulae, or perirectal abscesses. Because of the concern with carcinoma, the diagnosis often is made at surgery. However, laparoscopy or colonoscopy with biopsy may be sufficient to obtain diagnostic material(American Thoracic Society, 2000). Active pulmonary tuberculosis is uncommon in patients with tuberculous peritonitis. Because the process frequently coexists with other disorders, especially hepatic cirrhosis with ascites, the symptoms of tuberculosis may be obscured. The combination of fever and abdominal tenderness in a person with ascites should always prompt an evaluation for intraabdominal infection, and a paracentesis should be performed. However, this is often not diagnostic, and laparoscopy with biopsy is recommended if tuberculosis is suspected(American Thoracic Society, 2000).
              • Symptom -- Pain (American Thoracic Society, 2000):
                • Description: Tuberculous peritonitis frequently causes pain as its presenting manifestation, often accompanied by abdominal swelling. Fever, weight loss, and anorexia are also common(American Thoracic Society, 2000).
              • Symptom -- Abdominal swelling (American Thoracic Society, 2000):
                • Description: Tuberculous peritonitis frequently causes pain as its presenting manifestation, often accompanied by abdominal swelling. Fever, weight loss, and anorexia are also common(American Thoracic Society, 2000).
              • Symptom -- Fever (American Thoracic Society, 2000):
                • Description: Tuberculous peritonitis frequently causes pain as its presenting manifestation, often accompanied by abdominal swelling. Fever, weight loss, and anorexia are also common(American Thoracic Society, 2000).
              • Symptom -- Weight Loss (American Thoracic Society, 2000):
                • Description: Tuberculous peritonitis frequently causes pain as its presenting manifestation, often accompanied by abdominal swelling. Fever, weight loss, and anorexia are also common(American Thoracic Society, 2000).
              • Symptom -- Anorexia (American Thoracic Society, 2000):
                • Description: Tuberculous peritonitis frequently causes pain as its presenting manifestation, often accompanied by abdominal swelling. Fever, weight loss, and anorexia are also common(American Thoracic Society, 2000).
              • Symptom -- Abdominal tenderness (American Thoracic Society, 2000):
                • Description: Tuberculous peritonitis frequently causes pain as its presenting manifestation, often accompanied by abdominal swelling. Fever, weight loss, and anorexia are also common(American Thoracic Society, 2000).
            • Syndrome -- Pericardial tuberculosis (American Thoracic Society, 2000):
              • Description: The symptoms, physical findings, and laboratory abnormalities associated with tuberculous pericarditis may be the result of either the infectious process itself or the pericardial inflammation causing pain, effusion, and eventually hemodynamic effects. The systemic symptoms produced by the infection are quite nonspecific. Fever, weight loss, and night sweats are common in reported series. Symptoms of cardiopulmonary origin tend to occur later and include cough, dyspnea, orthopnea, ankle swelling, and chest pain. The chest pain may occasionally mimic angina but usually is described as being dull, aching, and often affected by position and by inspiration. Apart from fever, the most common physical findings are those caused by the pericardial fluid or fibrosiscardiac tamponade or constriction. Varying proportions of patients in reported series have signs of full-blown cardiac constriction when first evaluated. It is assumed that in these patients the acute phase of the process was unnoticed. In the absence of concurrent extracardiac tuberculosis, diagnosis of pericardial tuberculosis requires aspiration of pericardial fluid or, usually, pericardial biopsy(American Thoracic Society, 2000).
              • Symptom -- Pain (American Thoracic Society, 2000):
                • Description: The symptoms, physical findings, and laboratory abnormalities associated with tuberculous pericarditis may be the result of either the infectious process itself or the pericardial inflammation causing pain, effusion, and eventually hemodynamic effects(American Thoracic Society, 2000).
              • Symptom -- Effusion (American Thoracic Society, 2000):
                • Description: The symptoms, physical findings, and laboratory abnormalities associated with tuberculous pericarditis may be the result of either the infectious process itself or the pericardial inflammation causing pain, effusion, and eventually hemodynamic effects(American Thoracic Society, 2000).
              • Symptom -- Hemodynamic effects (American Thoracic Society, 2000):
                • Description: The symptoms, physical findings, and laboratory abnormalities associated with tuberculous pericarditis may be the result of either the infectious process itself or the pericardial inflammation causing pain, effusion, and eventually hemodynamic effects(American Thoracic Society, 2000).
              • Symptom -- Fever (American Thoracic Society, 2000):
                • Description: The systemic symptoms produced by the infection are quite nonspecific. Fever, weight loss, and night sweats are common in reported series(American Thoracic Society, 2000).
              • Symptom -- Weight loss (American Thoracic Society, 2000):
                • Description: The systemic symptoms produced by the infection are quite nonspecific. Fever, weight loss, and night sweats are common in reported series(American Thoracic Society, 2000).
              • Symptom -- Night sweats (American Thoracic Society, 2000):
                • Description: The systemic symptoms produced by the infection are quite nonspecific. Fever, weight loss, and night sweats are common in reported series(American Thoracic Society, 2000).
              • Symptom -- Cough (American Thoracic Society, 2000):
                • Description: Symptoms of cardiopulmonary origin tend to occur later and include cough, dyspnea, orthopnea, ankle swelling, and chest pain(American Thoracic Society, 2000).
              • Symptom -- Dyspnea (American Thoracic Society, 2000):
                • Description: Symptoms of cardiopulmonary origin tend to occur later and include cough, dyspnea, orthopnea, ankle swelling, and chest pain(American Thoracic Society, 2000).
              • Symptom -- Orthopnea (American Thoracic Society, 2000):
                • Description: Symptoms of cardiopulmonary origin tend to occur later and include cough, dyspnea, orthopnea, ankle swelling, and chest pain(American Thoracic Society, 2000).
              • Symptom -- Ankle swelling (American Thoracic Society, 2000):
                • Description: Symptoms of cardiopulmonary origin tend to occur later and include cough, dyspnea, orthopnea, ankle swelling, and chest pain(American Thoracic Society, 2000).
              • Symptom -- Chest pain (American Thoracic Society, 2000):
                • Description: Symptoms of cardiopulmonary origin tend to occur later and include cough, dyspnea, orthopnea, ankle swelling, and chest pain. The chest pain may occasionally mimic angina but usually is described as being dull, aching, and often affected by position and by inspiration(American Thoracic Society, 2000).
              • Symptom -- Cardiac tamponade (American Thoracic Society, 2000):
                • Description: Apart from fever, the most common physical findings are those caused by the pericardial fluid or fibrosiscardiac tamponade or constriction. Varying proportions of patients in reported series have signs of full-blown cardiac constriction when first evaluated(American Thoracic Society, 2000).
              • Symptom -- Cardiac constriction (American Thoracic Society, 2000):
                • Description: Apart from fever, the most common physical findings are those caused by the pericardial fluid or fibrosis-cardiac tamponade or constriction. Varying proportions of patients in reported series have signs of full-blown cardiac constriction when first evaluated(American Thoracic Society, 2000).
         5. Treatment Information:
            • Antibiotics for Active Pulmonary disease : Almost all recommended treatment regimens have two phases, on the basis of extensive evidence from controlled clinical trials. There is an initial intensive phase designed to kill actively growing and semidormant bacilli. This action shortens the duration of infectiousness with rapid smear and culture conversion after 23 months of treatment, in most cases (8090%). At least two bactericidal drugs, isoniazid and rifampicin, are necessary in the initial phase. Pyrazinamide given in the initial intensive phase allows the duration of treatment to be reduced from 9 to 6 months, but it offers no benefit if given past the second month to patients with drug susceptible tuberculosis. The addition of ethambutol benefits the regimen when initial drug resistance may be present or the burden of organisms is high. Several studies have shown that reliable prediction of which patients will take all prescribed medication by themselves is not possible; only direct observation can ensure that all drugs are taken. Directly observed treatment, in which a trained observer personally observes each dose of medication being swallowed by the patient, can ensure high rates of treatment completion, reduce development of acquired drug resistance, and prevent relapse. Non-adherence to tuberculosis treatment is known to have been common ever since the advent of chemotherapy in the 1950s. Thus, most tuberculosis treatment trials since that time have been carried out with direct observation. Randomised controlled trials have not shown a benefit from treatment observation; however, these trials have had a common shortcoming of less than optimum implementation of treatment observation, with rates of treatment success significantly below those of worldwide programmes of DOTS. Direct observation by trained individuals is the standard of practice in most countries and is a component of the five-point DOTS strategy recommended by WHO and IUATLD. Family members should not be relied on to ensure treatment completion. However, direct observation is only one feature of comprehensive tuberculosis care; sensitive, patient-centred treatment that includes direct observation is crucial for cure of patients and success of the programme.The initial phase of regimens including rifampicin should always be directly observed to ensure adherence and prevent emergence of resistance to rifampicin. The continuation phase eliminates most residual bacilli and reduces numbers of failures and relapses. At the start of the continuation phase there are low numbers of bacilli and less chance that drug-resistant mutants will be selected, and therefore fewer drugs are needed(Frieden et al., 2003).
              • Contraindicator: LIVER DISEASE: Drug-induced hepatitis can be fatal. WHO recommends that pyrazinamide should not be used in patients with known chronic liver disease. In decompensated liver disease, a regimen without rifampicin can be used. Streptomycin, ethambutol, and a reserve drug such as a fluoroquinolone can be used if treatment is necessary in patients with fulminant liver disease(Frieden et al., 2003). RENAL FAILURE: Normal doses of isoniazid, rifampicin, and pyrazinamide can be given in renal failure, since these drugs are eliminated almost entirely by biliary excretion or are metabolised into non-toxic compounds. In severe renal failure, patients receiving isoniazid should also receive pyridoxine to prevent peripheral neuropathy. Ethambutol can accumulate and cause optic neuropathy. Individuals on haemodialysis should receive primary drug treatment by direct observation after dialysis; several of the drugs are eliminated during dialysis(Frieden et al., 2003). PREGNANCY: Isoniazid, rifampicin, pyrazinamide, and ethambutol are not teratogenic, and WHO recommends their use in women who are pregnant. In the USA, pyrazinamide is not recommended for use during pregnancy except when alternative drugs are not available or are less effective. Active tuberculosis in pregnancy must be treated, because untreated disease will harm the mother and the unborn child more than standard drugs would. However, some reserve drugs may be more toxic; the risks and benefits of these drugs must be assessed for each woman separately, and in some instances treatment with reserve drugs should be deferred(Frieden et al., 2003). BREASTFEEDING: Most antituberculosis drugs can be used during breastfeeding. No data are available for ethionamide. Although data are lacking on amikacin and capreomycin, they are likely to be safe given their structural similarity to streptomycin and kanamycin (which are considered safe). Concentrations of antituberculosis drugs in breastmilk are too low to prevent or treat tuberculosis in infants. If tuberculosis is suspected in the child, he or she should be treated(Frieden et al., 2003).
              • Complication: GASTROINTESTINAL UPSET: nausea, vomiting, poor appetite, abdominal pain. Gastrointestinal reactions are common, particularly in the first few weeks of therapy. Many of the antituberculosis drugs can cause gastrointestinal upset. In the presence of gastrointestinal symptoms serum AST and bilirubin should be measured. If the AST level is less than three times the upper limit of normal, the symptoms are assumed not to be due to hepatic toxicity. However, if the AST level is three or more times the upper limit of normal the symptoms should be assumed to represent hepatic toxicity, and the patient should be evaluated as described below. The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity, is to change the hour of drug administration and/or to administer the drugs with food. If patients are taking daily DOT, the timing of the drug administration should be altered, preferably to be closer to mealtime. Alternatively, food can be taken at the time of DOT administration. (In many programs food is offered as an incentive with DOT.) Patients receiving self-administered therapy can take the medications at bedtime. If gastrointestinal intolerance persists it may be best for all medications to be taken with meals(American Thoracic Society et al., 2003). RASH: All drugs used in treating tuberculosis can cause a rash. The response to a patient with a rash depends on its severity. The rash may be minor, affecting a limited area or being predominantly manifested as itching, in which case antihistamines should be given for symptomatic relief, but all antituberculosis medications can be continued. A petechial rash may suggest thrombocytopenia in patients taking RIF. The platelet count should be checked and, if low, RIF hypersensitivity should be presumed to be the cause. RIF should be stopped and the platelet count monitored until it returns to baseline; RIF should not be restarted. If there is a generalized erythematous rash, especially if it is associated with fever and/or mucous membrane involvement, all drugs should be stopped immediately. If the patient has severe tuberculosis, three new drugs (e.g., an aminoglycoside and two oral agents) should be started. When the rash is substantially improved the medications can be restarted one by one, at intervals of 23 days. RIF should be restarted first (because it is the least likely to cause rash, and it is the most important agent), followed by INH, and then EMB or PZA. If the rash recurs the last drug added should be stopped. If no rash appears after the first three drugs have been restarted, the fourth drug should not be restarted unless the rash was relatively mild and the fourth drug is considered essential for therapy(American Thoracic Society et al., 2003). DRUG FEVER: Recurrence of fever in a patient who has been receiving therapy for several weeks should suggest drug fever, especially if the patient is showing microbiological and radiographic improvement. It should be noted, however, that fever from tuberculosis may persist for as long as 2 months after therapy has been initiated. Fever may also be a manifestation of a paradoxical reaction, especially in patients with HIV infection. The clinical hallmark of drug fever is that the patient looks and feels well despite having a high fever (often greater than 39C). There is no specific pattern to the fever. Eosinophilia may or may not be present. The first step in management of a possible drug fever is to ensure that there is no superinfection or worsening of tuberculosis. If these potential causes are excluded all drugs should be stopped. Drug-related fever usually will resolve within 24 hours. Patients with severe tuberculosis should be given at least three new drugs in the interim. Once the fever has resolved, the same protocol as described above for restarting drugs in the presenceof a rash should be followed(American Thoracic Society et al., 2003). HEPATITIS: Three of the first-line antituberculosis drugs, INH, RIF, and PZA, can cause drug-induced liver injury (AST level three or more times the upper limit of normal in the presence of symptoms, or five or more times the upper limit of normal in the absence of symptoms). If the AST level is less than 5 times the upper limit of normal, toxicity can be considered mild, an AST level 510 times normal defines moderate toxicity, and an AST level greater than 10 times normal (i.e., greater than 500 IU) is severe. In addition to AST elevation, occasionally there are disproportionate increases in bilirubin and alkaline phosphatase. This pattern is more consistent with rifampin hepatotoxicity. It is important to note that an asymptomatic increase in AST concentration occurs in nearly 20% of patients treated with the standard four-drug regimen. In the absence of symptoms therapy should not be altered because of modest asymptomatic elevations of AST, but the frequency of clinical and laboratory monitoring should be increased. In most patients, asymptomatic elevations resolve spontaneously. However, if AST levels are more than five times the upper limit of normal (with or without symptoms) or more than three times normal in the presence of symptoms, hepatotoxic drugs should be stopped immediately and the patient evaluated carefully. Similarly, a significant increase in bilirubin and/or alkaline phosphatase is cause for a prompt evaluation. Serologic testing for hepatitis A, B, and C should be performed and the patient questioned carefully regarding symptoms suggestive of biliary tract disease and exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medications. Drug-induced hepatitis is usually a diagnosis of exclusion but in view of the frequency with which other possible causes are present in any given patient, determining the cause may be difficult. Because the schedule for restarting antituberculosis medications is slower with hepatitis than for rash or drug fever it is generally prudent to give at least three nonhepatotoxic antituberculosis drugs until the specific cause of hepatotoxicity can be determined and an appropriate longer term regimen begun. The suspect antituberculosis medications should be restarted one at a time after the AST concentration returns to less than two times the upper limit of normal. (In patients with elevated baseline AST from preexisting liver disease, drugs should be restarted when the AST returns to near baseline levels.) Because RIF is much less likely to cause hepatotoxicity than is INH or PZA and is the most effective agent, it should be restarted first. If there is no increase in AST after about 1 week, INH may be restarted. PZA can be started 1 week after INH if AST does not increase. If symptoms recur or AST increases the last drug added should be stopped. If RIF and INH are tolerated, and hepatitis was severe, PZA should be assumed to be responsible and should be discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, therapy might be extended to 9 months(American Thoracic Society et al., 2003).
              • Drug Resistance: The treatment of patients whose organisms are resistant to standard drugs or who do not tolerate them is difficult. Reserve drugs are generally less effective and more toxic than standard therapy; they must be given daily, and some need to be taken several times a day. When devising a regimen for suspected or confirmed drug-resistant disease, several important principles must be followed. The initial regimen should include at least three drugs to which the bacilli are likely to be fully susceptible. Drugs should not be kept in reserve; the regimen most likely to be effective should be prescribed. Second-line drugs should be given daily under direct observation. Bacteriological results (smear and, if possible, culture) should be monitored. If susceptibility test results are available, a regimen can be chosen, based on the drugs to which the strain of M tuberculosis is susceptible. Most authorities recommend three or four oral drugs plus one injectable drug (such as capreomycin, amikacin, or kanamycin) to which the isolate is susceptible for 36 months, and then at least three effective oral drugs for 1518 months, for a total of 1218 months after culture conversion to negative. All efforts should be pursued to obtain an accurate susceptibility profile in patients for whom a standard regimen with first-line drugs fails, particularly if the treatment was given under direct observation. If drug susceptibility testing is not available, standard retreatment regimens can be used. Decisions must take into account the regimens the patient has received before, and whether the previous regimens were fully administered under direct observation and for how long. Longer use of injectable drugs is associated with improved outcomes, but long-term administration is commonly complicated by ototoxicity, nephrotoxicity, and local adverse reactions (eg, pain, induration, abscess formation). Details on the doses and major common adverse effects for the reserve drugs are given in table 4(Frieden et al., 2003).
            • Antibiotics for Active Extrapulmonary Disease : WHO recommends classification of the disease into severe and non-severe forms. Severe forms include meningeal and central-nervous-system tuberculosis, spinal tuberculosis, abdominal tuberculosis, bilateral pleural effusion, pericardial effusion, and bone and joint tuberculosis involving more than one site. WHO recommends category I regimens for severe forms and category III regimens for non-severe forms. All major organisations agree that some forms of disease, such as meningitis, may benefit from a longer treatment course. Steroids should be used for patients with large pleural effusions, pericardial disease, and meningitis, particularly with neurological impairment, since these drugs are likely to decrease morbidity and mortality in such cases(Frieden et al., 2003).
              • Contraindicator: Same as those from Active Pulmonary disease(Frieden et al., 2003).
              • Complication: Same as those from Active Pulmonary disease(Frieden et al., 2003).
              • Drug Resistance: Same as those from Active Pulmonary disease(Frieden et al., 2003).
            • Antibiotics for Latent TB Infection (LTBI) : Although a 9-mo regimen of isoniazid is the preferred regimen for the treatment of LTBI, a 6-mo regimen also provides substantial protection and has been shown to be superior to placebo in both HIV-negative and HIV-positive persons. In some situations, treatment for 6 mo rather than 9 mo may provide a more favorable outcome from a cost-effectiveness standpoint. Thus, based on local conditions, health departments or providers may conclude that a 6-mo rather than a 9-mo course of isoniazid is preferred(American Thoracic Society et al., 2000).
              • Contraindicator: Isoniazid is the most widely used of the antituberculosis agents -- it is bactericidal, relatively nontoxic, easily administered, and inexpensive(American Thoracic Society et al., 2000). Hepatitis is the most severe toxic effect of isoniazid, and alcohol consumption may increase toxicity. Peripheral neuropathy, caused by interference with metabolism of pyridoxine, is associated with isoniazid administration but is uncommon at a dose of 5 mg/kg. In persons with conditions in which neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition, and HIV infection), pyridoxine should be given with isoniazid. Pregnant women and persons with seizure disorders should also take both pyridoxine and isoniazid. Mild central nervous system effects are common with isoniazid and may necessitate adjustments in the timing of administration of the drug to enhance compliance. The interaction of isoniazid and phenytoin increases the serum concentration of both drugs. When these drugs are given concomitantly, the serum level of phenytoin should be monitored. No known interactions exist between isoniazid and the antiretroviral medications used for the treatment of HIV infection(American Thoracic Society et al., 2000).
              • Complication: (American Thoracic Society et al., 2000). Two recent studies reviewed data on patients who received prophylaxis according to the 1983 guidelines and found that the rate of fatal hepatitis was 1 to 1.7 per 100,000 for persons of all ages and approximately 2 per 100,000 for persons older than 35 years of age. This mortality rate is significantly lower than that found in the era before routine monitoring for liver toxicity(Salpeter et al., 1997).
              • Success Rate: The effectiveness of treatment, as measured by the decrease in TB among all persons participating in these trials, varied from 25 to 92%. However, when analysis was restricted to persons who were compliant with the medication, the protective efficacy was approximately 90%. Substantial protection was conferred even if pill taking was irregular but sustained, suggesting the possibility that intermittent treatment may be efficacious(American Thoracic Society et al., 2000).
              • Drug Resistance: Contacts of patients with isoniazid-resistant tuberculosis. No definitive data exist concerning treatment of contacts who have been exposed to patients with probable or confirmed isoniazid-resistant TB. A decision analysis and Delphi methodology have been used to recommend either rifampin alone or in combination with isoniazid or ethambutol when the risk of isoniazid-resistant infection is >50%(American Thoracic Society et al., 2000).
   4. Prevention:
      1. Bacille Calmette-Guerin (BCG) vaccine
         • Description: The history of BCG begins with pathogenesis experiments by Calmette and Guerin in the first decade of the 20th century. To study tuberculosis in cattle, they worked with cultures of bovine tubercle bacilli (M. bovis), which explains why our present vaccines against M tuberculosis are derived from closely related M. bovis. The importance of differences between M. tuberculosis and M. bovis in the derivation of a live, attenuated vaccine against human tuberculosis remains unknown. For optimum oral infection of cattle and guineapigs, Calmette added a detergent, specifically bile, to the culture medium, to prevent the bacteria from clumping. Within a few months, an unusual colony type arose, which was less virulent to the guinea pigs. Recognising from the work of Louis Pasteur that laboratory adaptation of bacteria is associated with attenuation of virulence towards the host species, Calmette continued the process of growing these bacteria in the presence of bile, for an astonishing 13 years. By changing the culture medium every 2 weekscalled passaginga total of 230 passages were achieved by 1921. During this time, this bacteria had a progressive decrease in virulence as measured in several different animals, including guinea pigs, rabbits, dogs, cows, horses, and monkeys; eventually an unidentified human being was injected with 44,000 bacteria intravenously to show that attenuation had successfully been accomplished(Behr, 2002), BCG vaccines have been given to billions of people since 1921, more than any other vaccine. Despite such a lengthy track record, BCG vaccination has also generated at least as much controversy as any other form of immunisation. Most importantly, the capacity to protect individuals against tuberculosis is still debated, since randomised clinical trials have provided estimates ranging from 80% protection to no benefit. Reasons for this widely varying degree of protection in trials have been reviewed in recent years. The other concern about BCG vaccination is the degree to which it can be safely used in countries with a high burden of HIV/AIDS. Traditionally, BCG vaccines have been considered among the safest in use. However, the true incidence of disease due to BCG strains (called BCG-itis or BCG-osis) is unknown since assays to characterise isolates as BCG are relatively new and are only recently being applied to clinical isolates(Behr, 2002),
         • Efficacy:
           • Rate: 50%(Brewer, 2000).
           • Duration: There is no clear evidence of a protective effect of BCG more than 10 years after vaccination(Sterne et al., 1998).
         • Contraindicator: There have been many reports of local complications of BCG vaccination in patients with HIV infection, especially abscesses, adenitis, and fistulae. These local complications of BCG vaccination have occurred in patients with both symptomatic and asymptomatic HIV infection. Symptomatic HIV-infected patients who are immunized with BCG vaccine have developed the devastating complication of disseminated disease(Talbot et al., 1997), In the retrospective review of disseminated BCG disease by Lotte et al., cellular immunodeficiency was identified as the chief risk factor for fatal outcome. Of the 60 total patients who were identified, 31 died. All patients who died had a definite or highly probable cellular immunodeficiency. Twenty-nine patients recovered. Eleven of these 29 patients also had a partial or serious immune defect(Talbot et al., 1997),
         • Complication: Serious complications of BCG vaccination, such as generalized lymphadenitis and disseminated disease, do occur in normal hosts, but these complications are exceptional(Talbot et al., 1997),
      1. Basic public health - sanatorium
         • Description: The lack of effective treatments prompted Hermann Brehmer in Europe in 1854 to establish the first sanatorium in the belief that exercise and altitude would serve to cure TB. Based on his own recovery from TB in New Yorks Adirondack mountains, Dr. Edward Livingston Trudeau in 1882 established the first sanatorium in the United States and initiated a public health movement featuring community participation, emphasis ion the outdoor life, and ordinances to improve sanitation and slum housing(Bloom and Murray, 1992),
   5. Model System:
      1. Guinea Pigs(Website 27)
         1. Model Host: Cavia porcellus.
            (McMurray et al., 1996),
         2. Model Pathogens: .
         3. Description: Early work with guinea pigs revealed that they were exquisitely susceptible to infection with virulent strains of M. tuberculosis following either injection or inhalation(McMurray et al., 1996), Studies of the fundamental aspects of the host-parasite relationship in pulmonary tuberculosis have been carried out over the past 25 years. It was demonstrated that guinea pigs could be infected reproducibly by the respiratory route with only a few (one to three) viable, virulent M. tuberculosis H37RV or Erdman(McMurray et al., 1996), The significance of the bacillemic phase of pulmonary tuberculosis, and our ability to study it in the guinea pig, cannot be overstated(McMurray et al., 1996), In addition to vaccination, other factors that have been shown to modify the pathogenesis of pulmonary tuberculosis in the guinea pig(McMurray et al., 1996), Chronic, moderate dietary protein deprivation has been shown to result in significant alterations in the pathogenesis of pulmonary tuberculosis in BCG-vaccinated animals(McMurray et al., 1996),
      1. Mouse(Website 28)
         1. Model Host: Mus musculus.
            (McMurray et al., 1996),
         2. Model Pathogens:
         3. Description: Rodents are not naturally subject to tuberculous disease (with the possible exception of the vole which may be infected with M. microti). However, mice can be readily infected in the laboratory with a variety of mycobacterial species and in recent years, inbred mice have been used increasingly in tuberculosis research, partly for economic reasons but also because of the availability of a variety of strains exhibiting different degrees of innate resistance to mycobacterial infection(McMurray et al., 1996),
      1. Rabbit(Website 29)
         1. Model Host: Oryctolagus cuniculus.
            (McMurray et al., 1996),
         2. Model Pathogens:
         3. Description: When infected by virulent human-type tubercle bacilli (M. tuberculosis), the rabbit shows more resistance than the mouse and much more resistance than the guinea pig. However, rabbits are fully susceptible to infection with virulent bovine-type tubercle bacilli (M. bovis). In fact, the rabbit is the classic animal used to distinguish between virulent human-type bacilli and virulent bovine-type bacilli. These animals always die when infected with the bovine strain and always live when infected with the human strain(McMurray et al., 1996), Tuberculosis in rabbits more closely resembled human tuberculosis than that produced in any other animal model. Lurie selectively bred susceptible and resistant rabbits. The susceptible rabbits developed a hematogenously spread tuberculosis resembling that found in infants and immunosuppressed adults (including those with AIDS). The resistant rabbits developed a cavitary-type of tuberculosis with bronchogenic spread, resembling that found in immunocompetent human beings(McMurray et al., 1996),
      1. Cynomolgus macaque(Website 38)
         1. Model Host: Macaca fascicularis.
            (Flynn et al., 2003),
         2. Model Pathogens:
         3. Description: Seventeen cynomolgus macaques were infected with M. tuberculosis strain Erdman in three separate experiments. Both male and female monkeys >4 years of age were used. The dose ranged from 15 to 25 CFU, delivered via bronchoscope to the right lower or middle lung lobe(Flynn et al., 2003), This report is a preliminary characterization of the initial studies in the non-human primate model of tuberculosis developed in our laboratory. Much more work needs to be done to begin to decipher patterns of disease, and the immune responses and pathology associated with each type of disease. The studies to date strongly indicate that the monkey model can recapitulate various important aspects of human tuberculosis, including primary disease as well as latent infection. This model will be useful for the study of the various phases of tuberculosis, and is the first tractable animal model of latent M. tuberculosis infection. This model is also likely to be useful for studying vaccines against tuberculosis, as well as for drug studies, particularly those drugs that might affect bacilli during latent infection. Although the cost and difficulty of containing the monkeys remain serious obstacles to the use of this model, there are facilities available now for this type of work. It is feasible to perform BSL3 M. tuberculosis research on monkeys, and to use this model to test hypotheses regarding the pathogenesis and immunology of this disease(Flynn et al., 2003),
2. Mammals (non-human)
   1. Taxonomy Information:
      1. Species:
         1. Mammalia (Website 39):
            • Common Name: Mammalia
            • GenBank Taxonomy No.: 40674
            • Description: (Montali et al., 2002). The primates generally and proboscids, represented in the zoo by African and Asiatic elephants, have the highest rates of infection among the mammals. The ungulates also show comparatively high rates of infection. The number of cases in the other groups of mammals are not in the order of magnitude that would cause great concern. The problem centers in four orders: Primates, Proboscidea, Perissodactyla, and Artiodactyla(Montali et al., 2002).
         2. Elephas maximus (Website 11):
            • Common Name: Elephas maximus
            • GenBank Taxonomy No.: 9783
            • Description: Tuberculosis (TB) has been recognized for over 2,000 yr as a disease of elephants. It has been most frequently reported in Asian elephants (Elephas maximus), all cultures have involved Mycobacterium tuberculosis(Mikota et al., 2001).
         3. Diceros bicornis (Website 12):
            • Common Name: Diceros bicornis
            • GenBank Taxonomy No.: 9805
            • Description: From 1997 to 2000, M. tuberculosis was identified in sixanimals at the Los Angeles Zoo(Oh et al., 2002). In September 1998, a black rhinoceros (Diceros bicornis) had a positive M. tuberculosis culture(Oh et al., 2002).
         4. Oreamnos americanus (Website 13):
            • Common Name: Oreamnos americanus
            • GenBank Taxonomy No.: 34873
            • Description: From 1997 to 2000, M. tuberculosis was identified in sixanimals at the Los Angeles Zoo(Oh et al., 2002). In July 1998, a Rocky Mountain goat (Oreamnos americanus) suffered deterioration associated with worsening pneumonia; the pathologic examination was consistent with TB, and culture confirmed M. tuberculosis(Oh et al., 2002).
         5. Pan troglodytes (Website 14):
            • Common Name: Pan troglodytes
            • GenBank Taxonomy No.: 9598
            • Description: From 1991 to 2001, M. tuberculosis was isolated from 12 animals, including(Michel et al., 2002). four chimpanzees (Pan troglodytes)(Michel et al., 2002).
         6. Addax nasomaculatus (Website 15):
            • Common Name: Addax nasomaculatus
            • GenBank Taxonomy No.: 59515
            • Description: From 1991 to 2001, M. tuberculosis was isolated from 12 animals, including(Michel et al., 2002). one addax (Addax nasomaculatus)(Michel et al., 2002).
         7. Tapirus terrestris (Website 16):
            • Common Name: Tapirus terrestris
            • GenBank Taxonomy No.: 9801
            • Description: From 1991 to 2001, M. tuberculosis was isolated from 12 animals, including(Michel et al., 2002). one Brazilian tapir (Tapirus terrestris)(Michel et al., 2002).
         8. Papio ursinus (Website 17):
            • Common Name: Papio ursinus
            • GenBank Taxonomy No.: 36229
            • Description: From 1991 to 2001, M. tuberculosis was isolated from 12 animals, including(Michel et al., 2002). one chacma baboon (Papio ursinus),(Michel et al., 2002).
         9. Semnopithecus entellus (Website 18):
            • Common Name: Semnopithecus entellus
            • GenBank Taxonomy No.: 88029
            • Description: From 1991 to 2001, M. tuberculosis was isolated from 12 animals, including(Michel et al., 2002). one Hanuman langur (Semnopithecus entellus)(Michel et al., 2002).
         10. Tragelaphus imberbis (Website 19):
             • Common Name: Tragelaphus imberbis
             • GenBank Taxonomy No.: 9947
             • Description: From 1991 to 2001, M. tuberculosis was isolated from 12 animals, including(Michel et al., 2002). one lesser kudu (Tragelaphus imberbis)(Michel et al., 2002).
         11. Tapirus indicus (Website 20):
             • Common Name: Tapirus indicus
             • GenBank Taxonomy No.: 9802
             • Description: From 1991 to 2001, M. tuberculosis was isolated from 12 animals, including(Michel et al., 2002). two Malayan tapirs (Tapirus indicus)(Michel et al., 2002).
         12. Redunca fulvorufula (Website 21):
             • Common Name: Redunca fulvorufula
             • GenBank Taxonomy No.: 59555
             • Description: From 1991 to 2001, M. tuberculosis was isolated from 12 animals, including(Michel et al., 2002). one mountain reedbuck (Redunca fulvorufula)(Michel et al., 2002).
         13. Canis familiaris (Website 24):
             • Common Name: Canis familiaris
             • GenBank Taxonomy No.: 9615
             • Description: Natural infection with Mycobacterium tuberculosis and Mycobacterium bovis in the dog has been reported for more than a century. Dogs can contract tuberculosis by living in intimate association with human beings or cattle that have the disease. Natural infection with M tuberculosis has rarely been reported in the dog in this country. [USA](Lui et al., 1980). Mycobacterium tuberculosis was isolated from lesions in five dogs as follows: lungs, three dogs; pericardium, one dog; liver, three dogs; and omentum, one dog(Lui et al., 1980).
         14. Oryx gazella (Website 25):
             • Common Name: Oryx gazella
             • GenBank Taxonomy No.: 9958
             • Description: Mycobacterium tuberculosis produced progressive disease in 2 oryxes and was the apparent cause of the death of 1 of the animals. This finding suggest that certain exotic ruminants may be more susceptible to M tuberculosis than the domestic ruminants -- cattle, sheep, and goats -- which appear to be relatively resistant(Lome et al., 1976).
         15. Cavia porcellus (Website 27):
             • Common Name: Cavia porcellus
             • GenBank Taxonomy No.: 10141
             • Description: Studies of the fundamental aspects of the host-parasite relationship in pulmonary tuberculosis have been carried out over the past 25 years. It was demonstrated that guinea pigs could be infected reproducibly by the respiratory route with only a few (one to three) viable, virulent M. tuberculosis H37RV or Erdman(McMurray et al., 1996).
         16. Mus musculus (Website 28):
             • Common Name: Mus musculus
             • GenBank Taxonomy No.: 10090
             • Description: Studies of the fundamental aspects of the host-parasite relationship in pulmonary tuberculosis have been carried out over the past 25 years. It was demonstrated that guinea pigs could be infected reproducibly by the respiratory route with only a few (one to three) viable, virulent M. tuberculosis H37RV or Erdman(McMurray et al., 1996).
         17. Oryctolagus cuniculus (Website 29):
             • Common Name: Oryctolagus cuniculus
             • GenBank Taxonomy No.: 9986
             • Description: Studies of the fundamental aspects of the host-parasite relationship in pulmonary tuberculosis have been carried out over the past 25 years. It was demonstrated that guinea pigs could be infected reproducibly by the respiratory route with only a few (one to three) viable, virulent M. tuberculosis H37RV or Erdman(McMurray et al., 1996).
         18. Macaca fascicularis (Website 38):
             • Common Name: Macaca fascicularis
             • GenBank Taxonomy No.: 9541
             • Description: Seventeen cynomolgus macaques were infected with M. tuberculosis strain Erdman in three separate experiments. All monkeys were judged to be infected by either conversion of tuberculin skin test or lymphocyte proliferation assays (LPA) to PPD(Flynn et al., 2003).
         19. Callithrix jacchus (Website 29):
             • Common Name: Callithrix jacchus
             • GenBank Taxonomy No.: 9483
             • Description: A 3-year-old marmoset (Callithrix jacchus) with serious loss of condition was presented to a veterinary practitioner. It had been kept as a companion animal from an early age. The veterinarian palpated a nodule in the abdomen of the marmoset, which died during an attempt to take a biopsy(Michel and Huchzermeyer, 1998). Moderate numbers of acid-fast rods were observed microscopically and M. tuberculosis was isolated from the specimen after inoculation onto slants of Loewenstein-Jensen medium(Michel and Huchzermeyer, 1998).
         20. Giraffa camelopardalis (Website 30):
             • Common Name: Giraffa camelopardalis
             • GenBank Taxonomy No.: 9894
             • Description: In 1974 at the Philiadelphia Zoological Gardens, M. tuberculosis was cultured from a Giraffe (Giraffa camelopardalis)(Montali et al., 2002).
         21. Aepyceros melampus (Website 31):
             • Common Name: Aepyceros melampus
             • GenBank Taxonomy No.: 9897
             • Description: In 1975 at the Philiadelphia Zoological Gardens, M. tuberculosis was cultured from an Impala (Aepyceros melampus)(Montali et al., 2002).
         22. Macaca mulatta (Website 32):
             • Common Name: Macaca mulatta
             • GenBank Taxonomy No.: 9544
             • Description: Rhesus monkeys are highly susceptible to infection with M. tuberculosis(Montali et al., 2002).
         23. Saimiri sciureus (Website 33):
             • Common Name: Saimiri sciureus
             • GenBank Taxonomy No.: 9521
             • Description: The squirrel monkey was a wild-caught, Brazilian-type adult male that was clinically normal when received 3 years prior to its death(Leathers and Hamm, 1976). The initial necropsy finding was numerous firm, white nodules in the spleen, characteristic of tuberculosis(Leathers and Hamm, 1976). Colonies of acid-fast bacteria grew on the Jensen-Lowenstein medium after 4 weeks' incubation. Cultures sent to the state laboratory were identified as Mycobacterium tuberculosis(Leathers and Hamm, 1976).
         24. Lemuridae (Website 35):
             • Common Name: Lemuridae
             • GenBank Taxonomy No.: 9446
             • Description: In our laboratory we have identified human tubercle bacilli in lesions from an elephant, from a sapajou, and from tapirs, as well as from such primates as the orangutan, lemur, and chimpanzee and from many monkeys(Karlson, 1960).
         25. Pongo pygmaeus (Website 36):
             • Common Name: Pongo pygmaeus
             • GenBank Taxonomy No.: 9600
             • Description: In our laboratory we have identified human tubercle bacilli in lesions from an elephant, from a sapajou, and from tapirs, as well as from such primates as the orangutan, lemur, and chimpanzee and from many monkeys(Karlson, 1960).
         26. Ateles sp. (Website 37):
             • Common Name: Ateles sp.
             • GenBank Taxonomy No.: 9506
             • Description: Our most serious outbreak of TB occurred in a group of seven spider monkeys (Ateles sp.) received from the Tarpon Springs Zoo on July 6, 1966(Montali et al., 2002). M. tuberculosis was isolated from three of the monkeys. Active TB shedding lesions were present in the intestines of three of the monkeys(Montali et al., 2002).
3. Birds
   1. Taxonomy Information:
      1. Species:
         1. Serinus canaria (Website 22):
            • Common Name: Serinus canaria
            • GenBank Taxonomy No.: 9135
            • Description: This report describes the findings of M. tuberculosis infection in a canary with extensive lung lesions(Hoop, 2002).
         2. Amazona aestiva (Website 22):
            • Common Name: Amazona aestiva
            • GenBank Taxonomy No.: 12930
            • Description: This report describes the findings of M. tuberculosisinfection in(Hoop, 2002). an Amazon parrot with chronic wasting(Hoop, 2002).
         3. Ara chloropterus (Website 26):
            • Common Name: Ara chloropterus
            • GenBank Taxonomy No.: 176013
            • Description: This report describes disseminated M. tuberculosis disease in another psittacine bird, a green-winged macaw, and notes a possible human source of the infection(Washko et al., 2002).
4. Reptiles
   1. Taxonomy Information:
      1. Species:
         1. Testudines (Website 34):
            • Common Name: Testudines
            • GenBank Taxonomy No.: 8459
            • Description: Microscopic examination revealed M. tuberculosis infection in isolates obtained from the liver and spleen of a turtle [translated from German](Stottmeier, 1963).

Not available for this pathogen.

NA

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Website 10: Human (Homo sapiens)

Website 11: Asian Elephant (Elephas maximus)

Website 12: Black rhinocerus (Diceros bicornis)

Website 13: Rocky Mountain Goat (Oreamnos americanus)

Website 14: Chimpanzee (Pan troglodytes)

Website 15: Addax nasomaculatus

Website 16: Brazilian Tapir (Tapirus terrestris)

Website 17: Chacma Baboon (Papio ursinus)

Website 18: Hanuman Langu (Semnopithecus entellus)

Website 19: Lesser Kudu (Tragelaphus imberbis)

Website 20: Malayan Tapir (Tapirus indicus)

Website 21: Mountain Reedbuck (Redunca fulvorufula)

Website 22: Canary (Serinus canaria)

Website 24: Dog (Canis familiaris)

Website 25: Oryx (Oryx gazella)

Website 26: Macaw (Ara chloropterus)

Website 27: Guinea Pig (Cavia porcellus)

Website 28: Mouse (Mus musculus)

Website 29: Rabbit (Oryctolagus cuniculus)

Website 29: Marmoset (Callithrix jacchus)

Website 30: Giraffe (Giraffa camelopardalis)

Website 31: Impala (Aepyceros melampus)

Website 32: Rhesus Monkey (Macaca mulatta)

Website 33: Squirrel Monkey (Saimiri sciureus)

Website 34: Turtles (Testudines)

Website 35: Lemur (Lemuridae)

Website 36: Orangutan (Pongo pygmaeus)

Website 37: Spider monkeys (Ateles sp.)

Website 38: Cynomolgus macaque (Macaca fascicularis)

Website 39: Mammals (Mammalia)

Website 6: Mycobacterium tuberculosis CDC1551, complete genome

Website 7: Mycobacterium tuberculosis CDC1551, complete genome

Website 8: Mycobacterium tuberculosis H37Rv, complete genome

Website 8: Mycobacterium tuberculosis H37Rv, complete genome

Woods et al., 1997: Woods GL, Fish G, Plaunt M, Murphy T. Clinical evaluation of difco ESP culture system II for growth and detection of mycobacteria. J Clin Microbiol. 1997; 35(1); 121-124. [PubMed: 8968892].

Woods, 2002: Woods GL. The mycobacteriology laboratory and new diagnostic techniques. Infect Dis Clin North Am. 2002; 16(1); 127-144. [PubMed: 11917810].

World Health Organization, 2003: World Health Organization . . 1-40. In: . Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2003. 2003. World Health Organization, Geneva, Switzerland.

Zanetti et al., 1997: Zanetti S, Ardito F, Sechi L, Sanguinetti M, Molicotti P, Delogu G, Pinna MP, Nacci A, Fadda G. Evaluation of a nonradiometric system (BACTEC 9000 MB) for detection of mycobacteria in human clinical samples. J Clin Microbiol. 1997; 35(8); 2072-2075. [PubMed: 9230384].

 

PathInfo: Lewis Bryan,

HazARD: (for the section of Lab Animal Pathobiology & Management)

PHIDIAS: Yongqun "Oliver" He

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