Latent Tuberculosis and Tuberculosis

Transcription

1 Latent Tuberculosis and Tuberculosis Postgraduate course: Diagnosis and treatment of tuberculosis, April 23, 2008 Hans L Rieder Department of Tuberculosis Control and Prevention International Union Against Tuberculosis and Lung Disease

2 Very rough estimates indeed Annual incidence (%) Prevalence (%) low high low High Infection with M tuberculosis Tuberculosis

3 All too cherished working hypotheses Once infected with Mycobacterium tuberculosis, infection persists for the remaining life time and may reactivate at any time. The antigens we have inform us about persisters

4 Kristian Andvord s break-through observation Andvord K F. Norsk Magasin for Lægevidenskapen 1930;91:642-60

5 Tuberculosis Notification Rates Among Males, Cross-Sectional Observations, Finland Notifications per 100,000 (log scale) Age (years) Härö AS. Tuberc Respir Dis Yearbook 1998;24:1-151

6 Tuberculosis Notification Rates Among Males, by Birth Cohort, Finland Notifications per 100,000 (log scale) Age (years) Härö AS. Tuberc Respir Dis Yearbook 1998;24:1-151

7 Andvord s conclusion Childhood experience with Mycobacterium tuberculosis predicts adult experience

8 Fate of M tuberculosis in calcified lesions Pulmonary Lymphatic Author Lesions Sterile Lesions Sterile Schmitz Rabinowitch Koenigsfeld Schroeder Opie Griffith Rubinstein Anders Saenz Total Percentage sterile Canetti G. Paris: Vigot Frères, 1939, 305 pp

9 Primary Infection and Reinfection at Autopsy Among Persons not Dying from Tuberculosis 100 Primary Reinfection Number of cases lesions 3 lesions 2 lesions 1 lesion Canetti G. Tubercle 1950;31:224-33

10 Observation and dilemma Observation Dilemma Bacilli are killed in the majority of cases following primary infection A large proportion of disease in adults is the result of reinfection Reconciling Andvord and Canetti

11 The Koch Phenomenon A primary infection leads to a delayed response and has often a mild and self-limited course A reinfection results commonly in a rapid response with tissue necrosis Drawings: Koch R. Mittheilungen aus dem Kaiserlichen Gesundheitsamte 1884;2:1-88. Phenomenon: Koch R. Dtsch Med Wochenschr 1891;17:101-2.

12 Reconciliation? Observation Observation Observation Reconciliation Childhood experience predicts adult mortality (Andvord) Tubercle bacilli from the primary infection are commonly eliminated (Canetti) Reinfection results in tissue destruction (Koch) Primary infection primes the child s immune system, re-infection in the previously infected adult leads in immunologic response to cavitary tuberculosis

13 Protection Afforded by BCG Vaccination in British School Children During Follow-up Protection (%) Year of follow-up D'Arcy Hart P, et al. Br Med J 1977;2:293-5

14 Birth cohort Primary infection Re-infection Cross-sectional Age Time / age Morbidity / mortality Remaining live bacilli Primary infection Andvord Canetti A Koch BMRC BCG Trial Progressive Re-infection Abortive C Time Time B D Tissue destruction BCG protection

15 Trying to fit observations. o o o A first infection is commonly overcome and frequently ends in the elimination of bacilli but primes the immune system for a decade or more A primed immune system may protect against subsequent re-infection or alternatively results in a severe tissue damaging response A positive tuberculin skin test is neither expression of living bacilli nor of protective immunity, it only reflects the immune response following prior infection

16 Repercussions and implications o Vaccination o Preventive therapy o Epidemiology

17 Risk of Tuberculosis During Follow-up by Size of Initial Tuberculin Skin Test Reaction, Malawi Relative risk (log scale) Ref Induration (mm) Fine PEM, et al. Lancet 1994;344:1245-9

18 Protection from BCG and from Small Tuberculin Skin Test Reactions During Follow-up, BCG Trial, Great Britain 80 BCG vaccinated Per cent protection Reacting to 100 TU only Year of follow-up D'Arcy Hart P, et al. Br Med J 1977;2:293-5

19 Growth of BCG in mice after sub-cutaneous vaccination Spleen 300 CFU of BCG Lymph nodes Lung Month after BCG vaccination Olsen AW, et al. Scand J Immunol 2004;60:273-77

20 Effect of Environmental Mycobacteria: Blocking and Masking Hypothesis Andersen P, et al. Nature Rev 2005;3:656-62

21 and another research question: If an individual is not protected by BCG, is tuberculosis more severe in this individual?

22 Factors Determining Effectiveness of Preventive Chemotherapy o o o o Probability of tuberculous infection Risk of tuberculosis given infection Efficacy of regimen Adherence to treatment

23 Distribution of Tuberculin Skin Test Reaction Sizes, Tanzania Schoolchildren, Number of reactors Cut-off > 4mm Prevalence: Sensitivity: Specificity: Pred Val Pos: Induration (mm) Data source: Styblo K, et al. TSRU Progress Report 1995;1:140-91

24 Distribution of Tuberculin Skin Test Reaction Sizes, Tanzania Schoolchildren, Number of reactors Cut-off >9mm Prevalence: Sensitivity: Specificity: Pred Val Pos: Induration (mm) Data source: Styblo K, et al. TSRU Progress Report 1995;1:140-91

25 Operating Characteristics of IGRAs Pai M, et al. Expert Rev Mal Diagn 2006;6:413-22

26 Prevalence (%) (log scale) Modeld Prevalence of Infection from Tuberculin Surveys and Measured IGRA Response, by Age, Japan Ratio Tuberculin surveys 5.4 IGRA survey Age group (years) Mori T, et al. Int J Tuberc Lung Dis 2007;11:1021-5

27 Effectiveness of Preventive Chemotherapy Probability of infection 0.80 Risk of tuberculosis Efficacy of regimen Adherence to treatment Overall effectiveness Number to treat to prevent 1 case

28 Thank you for your attention and patience