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APPENDIX 16
Mycobacterium tuberculosis

In the majority of infected individuals, the primary lesions of mycobacterium tuberculosis (TB) heal completely and leave no clinical evidence of prior infection except hypersensitivity to tuberculin. In some however, the primary infection progresses directly and evolves into a pneumonic process as the organisms spread through the bronchi or when a tuberculous node ruptures into a bronchus. Contiguous spread can cause infection in the pleural and pericardial spaces. At this stage, pleurisy, which is usually abrupt and resembles bacterial pneumonia with fever, chest pain, and shortness of breath are present.

Secondary tuberculosis is usually caused by organisms seeded in the apices of the lungs during the primary infection. These foci may evolve soon after seeding or after a long period of dormancy. Small patches of pneumonia develop around the foci. As the disease progresses, there is an insidious onset and development of nonspecific symptoms such as fatigue, fever, anorexia, night sweats, and general wasting. Cough and sputum denote more advanced disease.

Miliary tuberculosis occurs when the tubercle bacilli gain access to the lymphatics and bloodstream and seed distant organs. Miliary lesions may develop in almost any organ of the body, but of the most favored sites are bones and joints, the genitourinary tract, meninges, lymph nodes, and peritoneum. Miliary tuberculosis in its primary infection stage, when associated with meningitis, is responsible for deaths in young children.

See Appendix 28 for more information.



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Vaccines for the 21st Century: A Tool for Decisionmaking APPENDIX 16 Mycobacterium tuberculosis In the majority of infected individuals, the primary lesions of mycobacterium tuberculosis (TB) heal completely and leave no clinical evidence of prior infection except hypersensitivity to tuberculin. In some however, the primary infection progresses directly and evolves into a pneumonic process as the organisms spread through the bronchi or when a tuberculous node ruptures into a bronchus. Contiguous spread can cause infection in the pleural and pericardial spaces. At this stage, pleurisy, which is usually abrupt and resembles bacterial pneumonia with fever, chest pain, and shortness of breath are present. Secondary tuberculosis is usually caused by organisms seeded in the apices of the lungs during the primary infection. These foci may evolve soon after seeding or after a long period of dormancy. Small patches of pneumonia develop around the foci. As the disease progresses, there is an insidious onset and development of nonspecific symptoms such as fatigue, fever, anorexia, night sweats, and general wasting. Cough and sputum denote more advanced disease. Miliary tuberculosis occurs when the tubercle bacilli gain access to the lymphatics and bloodstream and seed distant organs. Miliary lesions may develop in almost any organ of the body, but of the most favored sites are bones and joints, the genitourinary tract, meninges, lymph nodes, and peritoneum. Miliary tuberculosis in its primary infection stage, when associated with meningitis, is responsible for deaths in young children. See Appendix 28 for more information.

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Vaccines for the 21st Century: A Tool for Decisionmaking DISEASE BURDEN Epidemiology For the purposes of the calculations in this report, the committee estimated that there are approximately 23,000 new cases of mycobacterium tuberculosis (TB) in the United States each year. It was assumed that incidence of TB infection increases with age. It is assumed that half the cases occur in people belonging to a high-risk group and half occur in people in multi-drug resistant areas. It was estimated that there are approximately 1,500 deaths associated with TB annually. See Table A16–1. Disease Scenarios For the purposes of the calculation in this report, the committee assumed that most cases of TB infection result in pulmonary disease. Extrapulmonary disease is seen in the remaining 12% of infected people. The health utility index (HUI) was assumed to range from 1.0 for treatment of asymptomatic people (described below) to .89 for the 9-month treatment phase for pulmonary TB and .72 for 20 days of severe extrapulmonary TB (including hospitalization). See Table A16–2. COST INCURRED BY DISEASE Table 16–3 summarizes the health care costs incurred by TB infections. For the purposes of the calculations in this report, it was assumed that costs are incurred for both active and asymptomatic (suspected and latent) cases of TB. It is assumed that for every case of confirmed, active TB disease, treatment for 3 to 5 asymptomatic (suspected or latent) cases of TB is required until TB infection is confirmed. Asymptomatic, latent infections require additional treatment. These treatments are assumed to include two visits to a general physician, three visits to a nurse, diagnostic evaluation, and medications. Although the model assumes that all suspected cases of TB undergo the care described above, it is assumed that adherence to a 6-month treatment regime for latent infections is not complete (e.g., that 40% of patients take medications for only 3 months). Health care costs incurred for pulmonary and extrapulmonary TB are assumed to involve hospitalization followed by 9 months of outpatient treatment. This follow-up involves monthly costs for a physician visit, diagnostic evaluation, and medication.

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A16–1 Incidence and Mortality Rates of TB Infections Age Groups Population Incidence Rates (per 100,000) % Distribution of Cases Cases <1 3,963,000 2.66 0.0046 106 1–4 16,219,000 2.66 0.0189 432 5–14 38,056,000 2.66 0.0445 1,014 15–24 36,263,000 4.69 0.0746 1,700 25–34 41,670,000 9.82 0.1794 4,090 35–44 42,149,000 9.82 0.1815 4,137 45–54 30,224,000 11.63 0.1542 3,515 55–64 21,241,000 11.63 0.1084 2,470 65–74 18,964,000 15.85 0.1318 3,005 75–84 11,088,000 15.85 0.0771 1,757 85+ 3,598,000 15.85 0.0250 570 Total 263,435,000 8.65 1.0000 22,795 Age Groups Population Mortality Rates (per 100,000) % Distribution of Cases Cases <1 3,963,000 0.00 0.0000 0 1–4 16,219,000 0.02 0.0020 3 5–14 38,056,000 0.00 0.0007 1 15–24 36,263,000 0.04 0.0102 15 25–34 41,670,000 0.18 0.0495 73 35–44 42,149,000 0.33 0.0928 137 45–54 30,224,000 0.50 0.1030 152 55–64 21,241,000 0.96 0.1382 204 65–74 18,964,000 1.65 0.2121 313 75–84 11,088,000 3.22 0.2419 357 85+ 3,598,000 6.14 0.1497 221 Total 263,435,000 0.56 1.0000 1,476 VACCINE DEVELOPMENT The committee assumed that it will take 15 years until licensure of a TB vaccine and that $360 million needs to be invested. Table 4–1 summarizes vaccine development assumptions for all vaccines considered in this report. VACCINE PROGRAM CONSIDERATIONS Target Population For the purposes of the calculations in this report, it is assumed that the target population for this vaccine is 500,000 high-risk people. 300,000 of those people are high-risk individuals in multi-drug-resistant areas. It was assumed that 90% of the selective high-risk population would utilize the vaccine and that

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A16–2 Disease Scenarios for TB Infection   No. of Cases % of Cases Committee HUI Values Duration (years) Total Deaths (from acute infection) 1,476   Total Cases (reported) 22,795   Asymptomatic—suspect suspect cases (treatment begun) 68,385 300.00% 1.0000 0.2500 (3 months) Asymptomatic—latent infection preventive treatment for latent infection 113,975 500.00% 1.0000 0.5000 (6 months) Pulmonary TB inpatient 20,060 88.00% 0.8700 0.0548 (20 days) Pulmonary TB outpatient 19,057 83.60% 0.8900 0.7500 (9 months) Extrapulmonary TB inpatient 2,735 12.00% 0.7200 0.0548 (20 days) Extrapulmonary TB outpatient 2,462 10.80% 0.8600 0.7500 (9 months) 60% of the targeted population in multi-drug-resistant areas would receive the vaccine. Vaccine Schedule, Efficacy, and Costs For the purposes of the calculations in this report, it was estimated that this vaccine would cost $50 per dose and that administration costs would be $10 per dose. Default assumptions of a 3-dose series and 75% effectiveness were accepted. Table 4–1 summarizes vaccine program assumptions for all vaccines considered in this report. RESULTS If a vaccine program for TB were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the QALYs gained would be $4,000. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the QALYs gained would be 1,300.

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A16–3 Health Care Costs Associated with TB Infection   % with Care Cost per Unit Units per Case Form of Treatment Asymptomatic—suspect   treated (detected in screening, etc.)   suspect cases: 3 months treatment until culture results available 100% $50 2.0 physician a   100% $25 3.0 nurse visit 100% $50 1.0 diagnostic a 100% $50 3.0 medication b Asymptomatic—latent   treated (detected in screening, etc.) 75% $50 3.0 physician a preventive treatment for latent infection: 6 months 75% $25 6.0 nurse visit estimated 60% complete treatment; rest complete half of treatment 100% $50 1.0 diagnostic a   60% $50 6.0 medication b: completes course 40% $50 3.0 medication b: completes half course Pulmonary TB   inpatient 100% $6,000 1.0 hospitalization   100% $100 3.0 physician b 100% $50 1.0 diagnostic a 25% $500 1.0 diagnostic c Pulmonary TB   outpatient 100% $50 9.0 physician a   100% $50 9.0 diagnostic a 100% $50 9.0 medication b Extrapulmonary TB   inpatient 100% $6,000 1.0 hospitalization   100% $100 3.0 physician b 100% $50 1.0 diagnostic b 25% $500 1.0 diagnostic c Extrapulmonary TB   outpatient 100% $50 9.0 physician a   100% $50 9.0 diagnostic a 100% $50 9.0 medication b If a vaccine program for TB were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the health care costs saved would be $100 million. Using committee assumptions of less-than-ideal efficacy and utilization and including time

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Vaccines for the 21st Century: A Tool for Decisionmaking and monetary costs until a vaccine program is implemented, the annualized present value of the health care costs saved would be $34.2 million. If a vaccine program for TB were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the program cost would be $90 million. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the program cost would be $35.9 million. Using committee assumptions of time and costs until licensure, the fixed cost of vaccine development has been amortized and is $10.8 million for a TB vaccine. If a vaccine program were implemented today and the vaccine were 100% efficacious and utilized by 100% of the target population, the annualized present value of the cost per QALY gained is −$3,000. A negative value represents a saving in costs in addition to a saving in QALYs. Using committee assumptions of less-than-ideal utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the cost per QALY gained is $9,500. See Chapters 4 and 5 for details on the methods and assumptions used by the committee for the results reported. READING LIST Brewer TF, Heymann SJ, Colditz GA, et al. Evaluation of Tuberculosis Control Policies Using Computer Simulation. JAMA 1996; 276:1898–1903. Brown RE, Miller B, Taylor WR, et al. Health-Care Expenditure for Tuberculosis in the United States. Archives of Internal Medicine 1995; 155:1595–1600. CDC. The Role of BCG Vaccine in the Prevention and Control of Tuberculosis in the United States. Morbidity and Mortality Weekly Report 1996; 45:1–18. CDC. Tuberculosis Morbidity—United States, 1995. Morbidity and Mortality Weekly Report 1996; 45:365–370. Haas DW, Des Prez RM. Mycobacterium Tuberculosis. In: Principles and Practice of Infectious Diseases. GL Mandell, JE Bennett, Dolin R eds. New York, NY: Churchill Livingstone, 1995, pp. 2213–2243. Miller B, Castro KG. Sharpen Available Tools for Tuberculosis Control, but New Tools Needed for Elimination. JAMA 1996; 276:1916–1917. Singh GK, Kochanek KD, MacDorman MF. Advance Report of Final Mortality Statistics, 1994. Monthly Vital Statistics Report 1996; 45. Smith MHD, Starke JR, Marquis JR. Tuberculosis and Opportunistic Mycobacterial Infections. In: Textbook of Pediatric Infectious Diseases. RD Feigin and JD Cherry eds. Philadelphia, PA: WB Saunder Company, 1992, pp. 1321–1362.