Is stool testing the answer to the problem of childhood TB diagnosis?

Stool Xpert® MTB/RIF test for the diagnosis of childhood pulmonary tuberculosis at primary clinics in Zimbabwe.

Chipinduro M, Mateveke K, Makamure B, Ferrand RA, Gomo E. Int J Tuberc Lung Dis. 2017 Feb 1;21(2):161-166. doi: 10.5588/ijtld.16.0357.

Objective: To evaluate the diagnostic performance of Xpert® MTB/RIF on stool samples from children with clinical suspicion of pulmonary tuberculosis (PTB) at primary care clinics.

Design: A cross-sectional diagnostic evaluation enrolling 5-16 year olds from whom one induced sputum (IS) sample was tested for microbiological TB confirmation. Results of a single stool sample tested using Xpert® were compared against microbiologically confirmed TB, defined as a positive result on sputum microscopy and/or culture and/or IS Xpert®.

Results: Of 222 children enrolled, 218 had complete microbiological results. The median age was 10.6 years (interquartile range 8-13). TB was microbiologically confirmed in 19/218 (8.7%) children. Of these, respectively 5 (26%), 9 (47%) and 15 (79%) were smear-, culture- and IS Xpert®-positive. Stool Xpert® was positive in 13/19 (68%) microbiologically confirmed cases and 4/199 (2%) microbiologically negative cases. Stool Xpert® detected 76.9% (10/13) of human immunodeficiency virus (HIV) infected and 50% (3/6) of non-HIV-infected children with microbiologically confirmed TB (P = 0.241).

Conclusion: Stool Xpert® is a potential alternative screening test for children with suspected TB if sputum is unavailable. Strategies to optimise the diagnostic yield of stool Xpert® assay need further study.

Abstract [1]  Full-text [free] access  [2]

Xpert® MTB/RIF on Stool is Useful for the Rapid Diagnosis of Tuberculosis in Young Children with Severe Pulmonary Disease

Walters E, van der Zalm MM, Palmer M, Bosch C, Demers AM, Draper H, Goussard P, Schaaf HS, Friedrich SO, Whitelaw A, Warren R, Gie RP, Hesseling AC. Pediatr Infect Dis J. 2017 Jan 31. doi: 10.1097/INF.0000000000001563. [Epub ahead of print]

Background: Tuberculosis (TB) continues to result in high morbidity and mortality in children from resource-limited settings. Diagnostic challenges, including resource-intense sputum collection methods and insensitive diagnostic tests, contribute to diagnostic delay and poor outcomes in children. We evaluated the diagnostic utility of stool Xpert® MTB/RIF (Xpert) compared with bacteriologic confirmation (combination of Xpert® and culture of respiratory samples).

Methods: In a hospital-based study in Cape Town, South Africa, we enrolled children younger than 13 years of age with suspected pulmonary TB from April 2012- August 2015. Standard clinical investigations included tuberculin skin test, chest radiograph and HIV testing. Respiratory samples for smear microscopy, Xpert® and liquid culture included gastric aspirates, induced sputum, nasopharyngeal aspirates and expectorated sputum. One stool sample per child was collected and tested using Xpert®.

Results: Of 379 children enrolled (median age, 15.9 months, 13.7% HIV-infected), 73 (19.3%) had bacteriologically confirmed TB. The sensitivity and specificity of stool Xpert® vs. overall bacteriologic confirmation were 31.9% (95% CI 21.84-44.50%) and 99.7% (95% CI 98.2-100%) respectively. 23/51 (45.1%) children with bacteriologically confirmed TB with severe disease were stool Xpert® positive. Cavities on chest radiograph were associated with Xpert® stool positivity regardless of age and other relevant factors (OR 7.05; 95% CI 2.16-22.98; p=0.001).

Conclusions: Stool Xpert® can rapidly confirm TB in children who present with radiologic findings suggestive of severe TB. In resource-limited settings where children frequently present with advanced disease, Xpert® on stool samples could improve access to rapid diagnostic confirmation and appropriate treatment.

Abstract access [3]

Editor’s notes: It has been known for a long time that Mycobacterium tuberculosis can be detected in stool specimens in some people with pulmonary TB disease. This is because sputum is often swallowed and M. tuberculosis bacilli can survive transit through the gastrointestinal tract. With the challenges of detecting TB in children, and the introduction of molecular diagnostic tools, there has been renewed interest in using stool specimens to improve TB diagnosis.

These two studies from southern Africa evaluated the diagnostic yield and accuracy of Xpert® MTB/RIF testing on stool specimens in children with symptoms compatible with intrathoracic TB. The study populations were different. The children in the South African study were younger than in the Zimbabwean study (median age 16 months vs. 10 years). In South Africa, only one in seven children was HIV positive whereas half the children were HIV positive in the Zimbabwean study. The South African study was conducted at hospital level whereas the Zimbabwean study was at primary health care clinics.

Despite these differences, the main findings were similar. Stool Xpert® was positive in six percent in South Africa and eight percent in Zimbabwe. Sensitivity of stool Xpert® compared to a single culture from induced sputum was 50% in South Africa and 67% in Zimbabwe. A single Xpert® test on stool was no better than a single Xpert® test on induced sputum. There was some evidence from both studies that sensitivity was higher in HIV positive children. However, in South Africa, sensitivity compared to any bacteriological confirmation was substantially lower (32%), as the reference standard included Xpert® and culture tests on multiple specimens. Sensitivity compared to the clinical decision to treat for TB was even lower (14%). This may have reflected the fact that all children in the South African study had chest X-rays and there were several children with intrathoracic lymph node disease.

What does this tell us about the role of Xpert® testing on stool for TB diagnosis in children? The evidence does not seem to provide strong support for scaling up stool Xpert® testing within standard diagnostic algorithms. As the South African study demonstrated, many of the children with positive Xpert® on stool were older children with more severe pulmonary disease. These are the children that may be more likely to produce sputum, and are the ones where we would want to make every effort to get respiratory specimens. This is especially the case in HIV-positive children, among whom there may be many possible diagnoses. Added to all this is the fact that processing and testing stool in the laboratory is not simple, meaning it might be difficult to scale up within decentralised laboratory systems.

It is encouraging that research groups are now addressing the challenge of TB diagnosis in children. It would seem that testing stool specimens for now does not really address the fundamental challenge in children, that they usually have paucibacillary disease often with little or no involvement of the lung parenchyma. The search must go on for better diagnostic tests for TB in children. 

Comorbidity [5], HIV Treatment [6]
Africa [7]
South Africa [8], Zimbabwe [9]
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