Quantity and Quality of Inhaled Dose Predicts Immunopathology in Tuberculosis

Abstract

Experimental animal models of tuberculosis (TB) have convincingly demonstrated that inhaled dose predicts immunopathology and survival. In contrast, the importance of inhaled dose has generally not been appreciated in TB epidemiology, clinical science, or the practice of TB control. Infectiousness of TB patients has traditionally been assessed using microscopy for acid-fast bacilli in the sputum, which should be considered only a risk factor. We have recently demonstrated that cough aerosol cultures from index cases with pulmonary TB are the best predictors of new infection among household contacts. We suggest that cough aerosols of M. tuberculosis are the best surrogates of inhaled dose, and we hypothesize that the quantity of cough aerosols is associated with TB infection versus disease. Although several factors affect the quality of infectious aerosols, we propose that the particle size distribution of cough aerosols is an important predictor of primary upper airway disease and cervical lymphadenitis and of immune responses in exposed hosts. We hypothesize that large droplet aerosols (>5 μ) containing M. tuberculosis deposit in the upper airway and can induce immune responses without establishing infection. We suggest that this may partially explain the large proportion of humans who never develop TB disease in spite of having immunological evidence of M. tuberculosis infection (e.g., positive tuberculin skin test or interferon gamma release assay). If these hypotheses are proven true, they would alter the current paradigm of latent TB infection and reactivation, further demonstrating the need for better biomarkers or methods of assessing TB infection and the risk of developing disease.

Keywords: TB transmission; cough aerosol; immunology; inhaled dose; latent infection; tuberculosis.

Figure 1

Schematic of Hypothesis 1 demonstrating the proposed concept that larger inhaled doses are more likely to produce primary TB disease (A) and lower doses are more likely to produce latent TB infection (B).

Figure 2

Increasing mortality and pathological changes in mice with increasing inhaled doses of Mycobacterium bovis. Data from Ref. (18).

Figure 3

Increasing rates of latent TB infection and active TB among health care workers with increasing degrees of estimated exposure to airborne M. tuberculosis. Data from Ref. (48).

Figure 4

Increasing rates of infection among household contacts of active cases of TB who produced larger cough aerosols (A). Increasing amounts of interferon gamma output in an interferon-gamma release assay among household contacts exposed to active cases of TB who produce larger cough aerosols (B) [from Ref. (68); please see that paper for details regarding numbers of subjects listed].

Figure 5

Schematic of Hypothesis 2 demonstrating immunization via the mucosa of the upper airway without the establishment of true TB infection in the alveolar region of the lung.

Figure 6

Wide range of particle size distributions of aerosols produced by voluntary coughing by healthy subjects. From Ref. (80).

Figure 7

Particle size distributions of cough aerosols from patients with active pulmonary TB [top panel; from Ref. (67)] and from cystic fibrosis patients with chronic P. aeruginosa infections [bottom panel; from Ref. (60)].