How Much Do Smear-Negative Patients Really Contribute to Tuberculosis Transmissions? Re-Examining an Old Question with New Tools

Abstract

Background: Sputum smear microscopy is a common surrogate for tuberculosis infectiousness. Previous estimates that smear-negative patients contribute 13-20% of transmissions and are, on average, 20-25% as infectious as smear-positive cases are understood to be high. Herein, we use an ideal real-world setting, a comprehensive dataset, and new high-resolution techniques to more accurately estimate the true transmission risk of smear-negative cases. Methods: We treated all adult culture-positive pulmonary TB patients as potential transmitters. Over a 15.5-year period we measured, as primary outcomes, the proportion of transmissions attributable to smear-negative sources and the relative transmission rate. First, we replicated previous studies by using only molecular (DNA) fingerprint clustering. Then, using a prospectively collected registry of TB contacts, we defined transmission events as active TB among identified contacts who either had a 100% DNA fingerprint match to the source case or a clinical diagnosis. To minimize omission of secondary cases who had not been identified as contacts, we undertook genome sequencing on temporally and geographically linked DNA fingerprint clusters. Findings: There were 1,176 cases, 563 smear-negative and 613 smear-positive, and 23,131 contacts. Replicating previous studies, the proportion of transmissions attributable to smear-negative source cases was 16% and the relative transmission rate was 0.19. With our combined approach, the proportion of transmission was 8% and the relative transmission rate became 0.10. Interpretation: After enhancing molecular data with conventional epidemiologic, spatial/temporal and genomic data, we found that smear-negative cases were approximately 50% less infectious than previously thought. The public health implications of this are substantial. Funding: Alberta Innovates Health Solutions Declaration of Interest: We declare no competing interests. Ethical Approval: The University of Alberta Health Research Ethics Board (HREB) Biomedical Panel for review of non-invasive studies involving humans provided approval for this study, protocol ID Pro00088408.