TB Intensive San Antonio, Texas December 1-3, 2010 TB Pathogenesis and Transmission Lynn Horvath, MD; TCID December 1, 2010 Tuberculosis Pathogenesis Lynn L. Horvath, MD, FACP, FIDSA Associate Professor of Medicine University of Texas Health Science Center - Tyler at the Texas Center for Infectious Disease
Outcomes of Exposure No infection (70%) Infection (30%) Of infected persons - No disease [latent] (90%) - Primary TB (5%) - Reactivation [post-primary] TB (5%) Latent Tuberculosis Infection No symptoms or signs of infection NOT infectious Positive tuberculin skin test T-cells respond to mycobacterial antigens Chest x-ray may be normal, or show granulomata, pleural or parenchymal scarring
PRIMARY AND POST-PRIMARY DISEASE
Pathogenesis of Pulmonary Acquired Tuberculosis Primary Disease Inhalation of Droplet Nuclei Localization to mid and lower areas of lung Pneumonia Multiplication Pleurisy Dissemination Acute hematogenous disease Meningitis PRIMARY TUBERCULOSIS
PRIMARY TUBERCULOSIS PRIMARY TUBERCULOSIS
PRIMARY TUBERCULOSIS Pathogenesis of Pulmonary Acquired Tuberculosis Post-Primary Disease Inhalation of Droplet Nuclei Localization to mid and lower areas of lung Multiplication Dissemination (Silent Bacteremia) Localization in areas of high oxygen concentration Apex of lung Kidney Development of Immunity Bone Brain Organisms killed Organisms walled off
Pathogenesis of Pulmonary Acquired Tuberculosis Post-Primary Disease Inhalation of Droplet Nuclei Localization to mid and lower areas of lung Multiplication Dissemination (Silent Bacteremia) Localization in areas of high oxygen concentration Apex of lung Kidney Development of Immunity Bone Brain Active disease Organisms killed Organisms walled off POST-PRIMARY TB
Who is most likely to become infected by Mycobacterium tuberculosis? Increased exposure Reduced resistance INFECTIOUS PARTICLES Only particles with < 5 μm aerodynamic diameter (infectious droplet nuclei) containing 1-3 tubercle bacilli can initiate infection (larger particles captured by mucociliary defenses)
LIKELIHOOD OF INFECTION Efficacy of droplet nuclei production - Coughing, talking, singing Bacillary burden of source case - AFB+ patients 4 times more infectious than AFB- patients Duration of exposure Ventilation - Closed rooms, crowding RESISTANCE TO INFECTION Innate immunity - Alveolar macrophages - Natural killer cells are lymphocytes that can lyse infected macrophages without prior exposure to the pathogen
Resistance to progression of infection to disease Adaptive immunity - T-lymphocytes, not B cells and antibodies - Th1 response (interleukin-12, interferongamma) Genetic susceptibility - IL-12 receptor, IFN-gamma receptor GRANULOMA FORMATION
GRANULOMA FORMATION GRANULOMA FORMATION
GRANULOMA FORMATION Latent Tuberculosis Infection 1) Bacteria are dormant (metabolically inactive). They later start to divide for reasons that are not clear. 2) Bacteria are metabolically active and dividing, but infection is controlled by the immune system. Disease develops when immunity wanes. Recent data in animals favor this hypothesis.
Latent infection Disease Recent infection HIV infection Chest x-ray evidence of prior TB Underweight by >10% Intravenous drug use ATS-CDC. Am J Respir Crit Care Med 2000;161:S221 Latent infection Disease Disease Relative risk Silicosis 30 Jejunoileal bypass 27-63 Renal transplant 37 Head or neck cancer 16 Renal failure 10-25.3 Diabetes 2.0-4.1 Gastrectomy 2-5 ATS-CDC. Am J Respir Crit Care Med 2000;161:S221-S247
Latent infection Disease Lung cancer Hematologic cancers TNFα inhibitors Prednisone >15 mg, > 4 weeks Other immunosuppressive drugs Latent infection Disease Smoking Never Smoked OR 1 Current Smoker OR 2.73 Ever Smoked OR 2.69 Am J Respir Crit Care Med 2009;180:475-480.
Am J Respir Crit Care Med 2009;180:475-480. Latent infection Disease Passive Smoking RR 1.64 Am J Respir Crit Care Med 2009;180:475-480. Arch Intern Med 2010;170(3): 287-292.
Summary Exposure can result in no infection, infection without disease (LTBI), primary TB or reactivation (post-primary) TB Factors that increase likelihood of infection Intensity and duration of exposure AFB+ source cases Ineffective innate immunity Innate immunity Macrophages, natural killer cells Summary Progression of infection to disease Adaptive immunity; T-cells, Th1 responses, IL-12 and IFN-gamma Recent data suggest that bacteria divide actively during latency but are contained by the immune system Recent infection and decreased immunity increase the risk that infection progresses to disease