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.

The transmission of Mycobacterium tuberculosis in high burden settings

“…39 Establishing infection or disease: The quantity and characteristics of the inhaled droplet predict clinical outcomes, with early experiments demonstrating that infectious dose predicts risk of progression to disease. 40 In the cough box experiments, the quantity of aerosolised MTB produced by individuals predicted infection in household contacts better than smear grade or time to culture positivity. 32 It has recently been proposed that larger droplets, settling in the upper airway, might result in immune memory and a positive test for infection but little risk of progression to disease.…”

Identification of incipient tuberculosis in household contacts. The relevance of tuberculosis exposure scores and contact investigations.

“…We limited the definition of incipient TB to subjects with Mtb-culture positive sputum or gastric aspirate (subjects <5 years) specimen. This definition almost certainly underestimates the number of incipient TB cases in our study but was suggested as providing the most objective and robust evidence of replicating Mtb which is certainly a pre-requisite for progressive disease and transmission (47)(48)(49)(50). We acknowledge though, that the relevance of Mtb-replication and transient excretion in the early phase of Mtb-infection reported in children (51) and which probably also occurs in adults, could be questioned, as successful containment and spontaneous recovery can be expected in an unknown proportion of subjects (13).…”

Identification of subclinical tuberculosis in household contacts. The relevance of tuberculosis exposure scores and contact investigations.

“…Therefore, we argue that our Mtb-culture based definition of subclinical TB is the most objective and robust tool for identification of subjects with high-risk for progressive disease and transmission (42)(43)(44)(45). We acknowledge though, that the relevance of Mtb-replication and transient excretion in the early phase of Mtb-infection reported in children (46), that probably also occurs in adults, could be questioned, as successful containment and spontaneous recovery can be expected in an unknown proportion of subjects (14).…”