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 to 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 diagnosed in the province of Alberta, Canada from 2003 to 2016 as potential transmitters. The primary data sources were the Alberta TB Registry and the Provincial Laboratory for Public Health. 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 molecular (DNA) fingerprint clustering. Then, using a prospectively collected registry of TB contacts, we defined transmission events as active TB amongst identified contacts who either had a 100% DNA fingerprint match to the source case or a clinical diagnosis. We supplemented our analysis with genome sequencing on temporally and geographically linked DNA fingerprint clusters of cases not identified as contacts.Findings There were 1176 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% (95% CI, 12−19%) and the relative transmission rate was 0.19 (95% CI, 0.14−0.26). With our combined approach, the proportion of transmission was 8% (95% CI, 3−14%) and the relative transmission rate became 0.10 (95% CI, 0.05−0.19).Interpretation When we examined the same outcomes as in previous studies but refined transmission ascertainment with the addition of conventional epidemiology and genomics, we found that smear-negative cases were »50% less infectious than previously thought.

A comparison of the chest radiographic and computed tomographic features of subclinical pulmonary tuberculosis

“…COVID-19 has shown that asymptomatic infection can be important in disease transmission 28 . In our subclinical patients smear-positivity and evidence of cavitation on chest radiograph, known predictors of the infectiousness of PTB, were uncommon 29 – 31 . However, cavitation and more extensive disease were much more common on CT scan.…”

Disease Transmission by Patients With Subclinical Tuberculosis

“…The smear status of the index patients was included in all analyses as studies have shown that smear-positive index patients are much more infectious than their smear-negative counterparts [ 20 , 26 ]. However, studies have suggested that the association between sputum smear status and transmission is inconsistent [ 10 , 27 ].…”

“…We used Poisson regression with robust standard errors to estimate the aRRs, as the number of children living with index patients in this study was relatively small, which could introduce bias in a logistic regression model [ 18 , 19 ]. Since smear-positive TB is generally more infectious than smear-negative TB [ 20 , 21 ], we took into account the smear status of the index patient. As smear status did not apply to background households, we combined in the first analysis the clinical and the smear status of index patients in a single variable with 5 values: background households with no index patient; subclinical, smear-negative; subclinical, smear-positive; clinical, smear-negative; and clinical, smear-positive.…”

Limitations of Chest Radiography in Diagnosing Subclinical Pulmonary Tuberculosis in Canada

“…It is conservatively estimated on the basis of past epidemiologic studies in the province that over the 16 years during which the cohort of subclinical patients was diagnosed, approximately 15,000 to 20,000 chest radiographs would have been read in connection with active case finding by field readers. 5 , 6 , 8 , 9 , 10 …”