In 2015, an estimated 10.4 million patients were newly diagnosed with tuberculosis (TB) worldwide, with 1.4 million cases resulting in death [1
]. To achieve the End TB 2035 target [1
] of a 90% reduction in the TB incidence rate by 2035, an acceleration of the present decline rate is urgently needed. Early and accurate diagnosis in high- and low-resource settings is the first pillar of the End TB strategy and is pivotal in enabling early treatment [2
One of the main reasons for the under-detection of TB is the limited availability of diagnostic methods [3
]. Moreover, when a diagnostic apparatus is available, many patients present with non-specific symptoms and negative laboratory exams. This delays diagnosis and aggravates prognosis.
The diagnosis of active TB has always used a composite approach, uniting radiology with three other technologies: Microscopy (sputum smears), culture-based methods, and molecular tests [4
]. Unfortunately, facilities using these technologies are not always available in resource-limited settings, especially in peripheral health centers.
Point-of-care chest ultrasonography (CUS), intended for lung, pleural, and mediastinal ultrasonography, is becoming an attractive, non-invasive medical imaging modality in both affluent and resource-limited settings [5
]. A recent consensus standardized terminology and indications, regarding critical care lung ultrasound [6
]—a method which evolved as a highly sensitive and specific imaging tool for diagnosing chest conditions, such as pneumothorax, pneumonia, and pulmonary edema. Resource-limited settings are of special interest, as radiological equipment and expertise are scarce, or even absent, due to their high costs or poor maintenance. A focused assessment of extra-pulmonary TB has been also proposed [7
]. However, the role of lung, and more broadly, chest ultrasound in defining TB has been scarcely investigated. It is currently unclear if CUS could play a clinically-relevant role in diagnosing or excluding active tubercular chest lesions.
The aim of this review is to describe existing studies that have used CUS for the diagnosis of thoracic TB, to ascertain whether it represents a useful tool for the diagnosis and follow up of TB.
This systematic review was conducted, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) [8
] statement. The methodological quality of each study was critically evaluated, using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS 2) [9
2.1. Search Strategy
Two investigators (FG and LP), independently and unaware of the other investigator’s decisions, searched PubMed, EMBASE, and Scopus for studies assessing the role of lung ultrasound in thoracic TB. Searches were carried out without language restrictions and from the database’s inception until April 2017. Any inconsistencies that remained after discussion were resolved by consensus with a third author (NV), available for mediation. In PubMed, we used the following search strategy: (tuberculosis) AND (ultrasound OR ultrasonography) OR (miliary OR lung OR chest) AND/OR (recovery OR pattern OR diagnosis OR effusion). A similar search strategy was run in EMBASE and Scopus. Reference lists of included articles and those relevant to the topic were hand-searched for identification of additional, potentially-relevant articles.
2.2. Study Selection
We included all studies reporting patient data (including original studies, case-reports, and case series) using chest ultrasound for the diagnosis or management of any form of thoracic tuberculosis, namely its pulmonary, pleural, mediastinal, and miliary forms. Studies were excluded if they (1) used ultrasound for non-thoracic organs or (2) used endoscopic ultrasound. Studies were included, irrespective of the methodology employed. This was to ensure that a comprehensive understanding of the available evidence was achieved.
2.3. Data Extraction and Analysis
The two authors (FG, LP) independently extracted data, using a standardized spreadsheet. Any disagreement was resolved by consensus with a third author (DP). The following information was extracted: (i) Study population characteristics (i.e., author, year, number of participants, mean age, and percentage of females); (ii) study design and inclusion criteria; (iii) details of the ultrasound procedure; (iv) diagnostic criteria used for detecting TB and the final diagnosis made (pulmonary, pleural, or mediastinal TB); and (v) the anatomical site of investigation (pleural cavity, mediastinum, or lung).
The extracted information was organized in tables, describing each study’s characteristics, methods, and its main results. Patient characteristics—such as age, number of participants, and number of female cases—were summarized as the mean or proportions, where appropriate. Due to the different design of the studies included, the purely descriptive aim of 8 of the 12 studies, and the high heterogeneity of the outcomes reported, we decided not to meta-analyze the selected studies, instead reporting the main findings as descriptive results. Where some degree of diagnostic accuracy was reported, we calculated it as the percentage of patients with a positive ultrasound (US) examination, over the total of confirmed or suspected TB patients.
The main finding of our systematic review is that the few available studies on chest ultrasound have focused on five fields of interest: detection of pleural effusion, assessment of residual pleural thickening, the helpfulness of trans-thoracic needle biopsy, assessment of mediastinal lymphadenopathies, and detection of pulmonary involvement in miliary TB. To our knowledge, this is the first review summarizing evidence for the use of chest ultrasound in the diagnosis of thoracic tuberculosis.
Surprisingly, apart from a single reported case, we found no study analyzing parenchymal ultrasound patterns, typical of pulmonary TB. Considering the pulmonary involvement of TB has been extensively studied by other radiological means [22
], we expected to find evidence to include or exclude CUS as an alternative imaging technique in active TB. In the wider field of chest ultrasound, lung ultrasound (LUS) has gained acceptance for the diagnosis of consolidations and interstitial syndromes [23
], hence its potential role in defining TB-related, pneumonic infiltrates. However, there appears to be scant available data at the moment, analyzing the use of LUS in the definition of TB parenchymal infiltrates.
The only study that attempted to report lung patterns describes the presence of B-lines and subpleural granularity, but only enrolled ten patients with miliary TB, which is distinct from pulmonary TB. Additionally, B-lines are, by definition, a highly non-specific sign of interstitial involvement, hence their role must be confirmed before LUS can be used to differentiate TB from other interstitial and alveolar lung diseases. Further, the presence, severity, and distribution of subpleural consolidation in patients with sole pulmonary involvement is still unknown.
There is an increasing interest in employing chest ultrasound in low- and middle-income countries [24
]. Chest ultrasound has a relatively steep learning curve: It is ionization-free and is increasingly available [25
] at reasonable costs. Moreover, it can be portable and operated with rechargeable batteries. Ultrasound gel, the only routine supply item needed, can easily be produced locally [26
], thus making it an attractive option in resource-limited settings. On the other hand, inter-observer variability and diagnostic errors represent important pitfalls, and should be investigated specifically for TB. While the conditions for a wider implementation are favorable, none of the studies were performed in low-income countries. This observation, added to the paucity of available evidence, indicates that the use of CUS for the diagnosis of thoracic TB is still a clinical niche.
No conclusions can be drawn on diagnostic accuracy, as we did not find any clinical trial that compared CUS versus other imaging modalities. In the search for early diagnosis techniques, high negative predictive values become an important endpoint to target. If the benefits of point of care ultrasonography can be transposed to the diagnosis and management of TB—a disease that may yield highly unspecific signs [12
]—it remains yet to be challenged by an adequately-powered, diagnostic trial.
The strength of our review stems from the strict search performed and pragmatic clinical questioning. Limitations of the review are the paucity of available data and extreme heterogeneity of the studies included, in terms of aim, methodology, and outcomes. The low or unclear quality of many of the included studies also greatly limits generalizations. Additionally, only five studies [12
] compared the result of the CUS technique to a reference standard for the diagnosis of TB. Most importantly, no prospective studies comparing CUS to other imaging modalities in diagnosing TB were identified.
There is a striking scarcity of studies analyzing the use of chest ultrasound as an imaging technique to aid TB diagnosis. CUS is a promising imaging technique for the detection of TB-related effusion, residual pleural thickening, mediastinal lymphadenopathy, and trans-thoracic biopsy guidance. CUS may prove beneficial, especially in low-income countries, where incidence is high and radiological techniques are scarce. Further research is urgently needed to define pulmonary TB patterns, the feasibility of CUS, and diagnostic accuracy.