Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis

Ray Y Chen ,Xiang Yu,Jing Wang,Ruanqing Zhang,Xiaowei Jin,Shouguo Pan,Joel Vincent,Rodney Dawson,Hong Zhu,Bronwyn Smith,Friedrich Thienemann,Kriti Arora,Xin Liu,Jingcai Gao,Ying Cai,Gerhard Walzl,Stephanus T Malherbe ,Yue Qu ,Lisa C Goldfeder ,Andreas H Diacon ,Robert J Wilkinson ,Michèle Tameris ,Clifton E Barry

doi:10.1016/s2666-5247(21)00058-6

Abstract

SummaryBackgroundDirect bronchial spread of tuberculosis was extensively described in pre-antibiotic human pathology literature but this description has been overlooked in the post-antibiotic era, in which most pathology data come from animal models that emphasise the granuloma. Modern techniques, such as [18F]2-fluoro-2-deoxy-D-glucose (FDG) PET-CT scans, might provide further insight. Our aim was to understand normal early tuberculosis resolution patterns on pulmonary PET-CT scans in treated patients with tuberculosis who were subsequently cured.MethodsIn this observational analysis, we analysed data from PredictTB, an ongoing, prospective, randomised clinical trial that examined sequential baseline and week 4 FDG-PET-CT scans from participants successfully treated (sputum culture negative 18 months after enrolment) for drug-susceptible pulmonary tuberculosis in South Africa and China. Participants who were aged 18–75 years, GeneXpert MTB/RIF positive for tuberculosis and negative for rifampicin resistance, had not yet started tuberculosis treatment, had not been treated for active tuberculosis within the previous 3 years, and met basic safety laboratory criteria were included and participants with diabetes, HIV infection, or with extrapulmonary tuberculosis including pleural tuberculosis were excluded. Scans were assessed by two readers for the location of tuberculosis lesions (eg, cavities and consolidations), bronchial thickening patterns, and changes from baseline to week 4 of treatment.FindingsAmong the first 124 participants (enrolled from June 22, 2017, to Sept 27, 2018) who were successfully treated, 161 primarily apical cavitary lesions were identified at baseline. Bronchial thickening and inflammation linking non-cavitary consolidative lesions to cavities were observed in 121 (98%) of 124 participants' baseline PET-CT scans. After 4 weeks of treatment, 21 (17%) of 124 participants had new or expanding lesions linked to cavities via bronchial inflammation that were not present at baseline, particularly participants with two or more cavities at baseline and participants from South Africa.InterpretationIn participants with pulmonary tuberculosis who were subsequently cured, the location of cavitary and non-cavitary lesions at baseline and new lesions at week 4 of treatment suggest a cavitary origin of disease and bronchial spread through the lungs. Bronchial spread from cavities might play a larger role in the spread of pulmonary tuberculosis than has been appreciated. Elucidating cavity lesion dynamics and Mycobacterium tuberculosis viability within cavities might better explain treatment outcomes and why some patients are cured and others relapse.FundingBill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership, China Ministry of Science and Technology, National Natural Science Foundation of China, and National Institutes of Health.TranslationsFor the Chinese, Afrikaans and Xhosa translations of the abstract see Supplementary Materials section.

Highlights

Tuberculosis infection has traditionally been described in two stages, latent or active
Driven by data from rabbits and non-human primates, it is thought that Mycobacterium tuberculosis bacilli contained in granulomas begin to replicate and erode into a bronchus, forming a cavity that allows transmission until symptoms emerge and a patient is treated.[1,2]
Pathologists of that time recognised that primary tuberculosis infection generally did not lead to active tuberculosis but rather was most often controlled within a granuloma or the hilar lymph nodes

Summary

Introduction

Tuberculosis infection has traditionally been described in two stages, latent or active. In the past 5 years, reviews of tuberculosis, have begun to view infection more as a continuum rather than distinct, dichotomous stages. Pathologists of that time recognised that primary tuberculosis infection generally did not lead to active tuberculosis but rather was most often controlled within a granuloma or the hilar lymph nodes. Multiple authors noted that cavities formed from a caseous focus of infection that progressed to liquefactive necrosis. When such a lesion expanded and eroded into a bronchus, air Lancet Microbe 2021; 2: e518–26

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