Transmission of Mycobacterium tuberculosis

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1 Transmission of Mycobacterium tuberculosis Charles Daley, MD National Jewish Health

2 Disclosures Advisory Board Horizon, Johnson and Johnson, Otsuka and Spero Investigator Insmed

3 Objectives After attending this lecture, participants should be able to describe: how M. tuberculosis is transmitted which factors affect the transmission of M. tuberculosis the model of transmission and pathogenesis the factors that contribute to TB outbreaks

4 Outline A brief history of our understanding of the transmission of M. tuberculosis Factors associated with transmission Model of transmission and pathogenesis Tuberculosis control strategies

5 Transmission of M. tuberculosis In approaching the consumptive one breathes pernicious air. One takes the disease because there is in this air something diseaseproducing. Aristotle BC

6 Historical Perspective on the Cause of TB Hippocrates BC Aristotle BC Hereditary Etiology Contagiousness of Phthisis Galen 129 to 216 AD Danger of living with a phthisis case

7 Historical Perspective on the Cause of TB-19th Century Laennec - miliary granule, infiltrate, caseous mass - TB Villemin - transmission of TB to guinea pigs, 1865 Koch - demonstration of Bacillus tuberculosis, 1882

8 Contagiousness of TB Difficult to Accept Low infectiousness - prolonged contact required Low pathogenicity - few infected developed TB High virulence - up to half of cases died Variable, prolonged latency - disease long after exposure Variable manifestations - phthisis, pleuritis, scrofula, meningitis, renal disease, infertility

9 Audience Response Question Which of the following scenarios is associated with the greatest risk of transmission of M. tuberculosis? A. Autopsy in patient with pulmonary TB B. Bronchoscopy in patient with pulmonary TB C. Smear positive pulmonary TB D. Laryngeal TB

10 Transmission via Aerosol

11 Riley s Experiments Proving Droplet Nucleus Theory TB patients were hospitalized on a 6-bed ward sealed off from the rest of the hospital Guinea pigs breathed air from exhaust ducts from the TB ward 134 guinea pigs became infected over 4 years, as indicated by positive tuberculin conversions, and finding tubercles on post-mortem exams It was estimated that there was one infectious droplet nucleus per 12,000 cubic feet Ultraviolet light prevented infection of the guinea pigs

12 Riley s Experiments Proving Droplet Nucleus Theory

13 Infectious Particle for TB - Droplet Nucleus Microscopic droplets generated by coughing, sneezing, speech, singing Evaporate to droplet nuclei (1 to 3 microns) Capable of reaching alveolus Droplet nuclei remain suspended in the air for up to 1 hr Droplet nuclei disperse with the flow of air

14 Transmission of Tuberculosis Generation of Droplet Nuclei One cough produces 500 droplets The average tuberculosis (TB) patient generates 75,000 droplets per day before therapy This drops to 25 infectious droplets per day within 2 weeks of effective therapy

15 Cough Aerosols vs Sputum Smear 96 smear & culture positive patients 43/96 (45%) produced aerosols high aerosol production was the only risk associated with new infection (TST and/or QFT conversion) Jones-Lopez AJRCCM 2013; 187: 1007

16 Transmission of Tuberculosis Generation of Infectious Particles TB Scenario AFB/hr Time to infected Pulmonary days Laryngeal hours Bronchoscopy hours Autopsy hours

17 Transmission of Tuberculosis CASE Site of TB Cough Bacillary load Treatment Ventilation Filtration U.V. light CONTACT Closeness and duration of contact Immune status Previous infection

18 Other Modes of Transmission are Unusual Congenital - transplacental infection occurs (rare) Innoculation - "prosector s wart" Gastrointestinal - bovine TB, heavy inoculums Not due to contamination of food Other aerosols - laboratory, wound debridement

19 Transmission of Tuberculosis From A Patient with a Hip Abscess Patient Room Outpatient recovery Hutton MD, et al. JID. 1990;161:286

20 Factors Associated with Transmission: TB Source Case Sputum AFB smear + : bacilli/ml 4- to 5-X as infectious Cavities : sputum volume up to > 100 ml/day Presence of cough - spontaneous or induced Laryngeal TB - usually with cavitary TB/cough; few AFB on vocal cords More virulent strains of TB - some markers found, but controversial

21 Indices of Infectiousness Household Contacts Source-Case Variables Tuberculin Reactors (%) Radiographic extent of disease Minimal 16.1 Moderately advanced 28.3 Far advanced 61.5 Bacteriologic status Smear, culture 14.3 Smear, culture Smear +, culture Mean 8-hour overnight cough count < > Loudon RG. ARRD 1969;99:109

22 Prevalence of Infection Among Contacts by Bacillary Load of Source Case Age Smear + Smear Smear General (yrs) Culture + Culture + Culture Population Grzybowski S. BIUAT 1975;60:90

23 Prevalence of Infection Among Contacts by Bacillary Load of Source Case Age Smear + Smear Smear General (yrs) Culture + Culture + Culture Population Grzybowski S. BIUAT 1975;60:90

24 Prevalence of Infection Among Contacts by Bacillary Load of Source Case Age Smear + Smear Smear General (yrs) Culture + Culture + Culture Population Grzybowski S. BIUAT 1975;60:90

25 Effects of Therapy on Transmission of M. tuberculosis Log No. MTB Weeks Begin Treatment

26 Infectivity of Tuberculosis Patients on Chemotherapy 21 patients with pulmonary TB discharged after about 2 weeks of chemotherapy (2-36 days). 20/21 had positive sputum cultures on discharge, 16/21 had cavitary disease Of 72 household contacts initially tuberculinnegative, none converted their skin tests subsequently (23 of 72 treated with INH) Conclusion: Tuberculosis patients on chemotherapy can be discharged safely without additional risk to contacts Brooks, 1973

27 Factors Associated with Transmission: The Environment Volume of air in exposure setting Frequency of air exchange (dilution) UV irradiation, natural or artificial High efficiency filtration

28 Ventilation Number Infected vs. Ventilation IPH 1.25 IPH 250 IPH Infectious particles/hour 60 IPH Ventilation (CFM/occupant)

29 UVGI Removal of Aerosolized BCG by UVGI 10 2 Colonies Minutes UV off: 2 ACH 17 W UV: 12 ACH Adapted from Riley, et al. ARRD 1976;113:417

30 Tuberculin Reactivity Among Contacts by Index Status Contact status Index Status Household Casual (n=858) (n=4207) Sm +, Cx % 3.7% Sm, Cx + 1.1% 0.2% Van Geuns, et al. BIUAT 1975;50:107

31 Frequency of Reinfection as Cause of Recurrent TB Study (by incidence) Site Genotyping Method N (%) with reinfection Low De Boer, 2003 Jasmer, 2004 Dobler, 2009 Intermediate Bandera, 2001 Caminero, 2001 Garcia, 2002 Martin, 2011 High Van Rie, 1999 Verver, 2005 Andrews, 2008 Aralambous, 2008 Crampin, 2010 Narayanan, 2010 Netherlands US/Canada Australia Italy Spain Spain Spain South Africa South Africa South Africa South Africa Malawi India IS6110 RFLP IS6110 RFLP IS6110, spoligotype, MIRU IS6110 RFLP IS6110 RFLP DRE-PCR MIRU-VNTR Spoligotype IS6110 RFLP IS6110 RFLP IS6110 RFLP IS6110 RFLP IS6110, spoligotype, MIRU 29/183 (16%) 3/75 (4%) 4/15 (27%) 5/32 (16%) 8/18 (44%) 14/43 (33%) 8/40 (20%) 12/16 (75%) 28/68 (41%) 17/17 (100%) 11/16 (68%) 1/16 (6%) HIV- 12/23 (52%) HIV + 2/23 (9%) HIV- 22/25 (88%) HIV+

32 Transmission and Pathogenesis of Tuberculosis Exposure No infection (70%) Infection (30%) Early progression (5%) Containment (95%) Late progression (5%) Continued containment (90%)

33 Transmission and Pathogenesis of Tuberculosis Affect of HIV Exposure No infection (<70%?) No infection (70%) Early progression (40%) Early progression (5%) Infection (30%) Infection (>30%?) Containment (95%) Containment (60%) Late progression (5-10%/yr) Late progression (5%) HIV positive HIV negative Continued containment (90%) Continued containment (0%?)

34 Tuberculosis Control Strategies Prompt identification and treatment of TB cases or suspects Rapid identification of contacts to infectious cases Treatment of high-risk individuals with presumed or documented latent TB infection Reduce the risk of exposure to droplet nuclei

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