Letter: Crohn's Disease With Latent Tuberculosis Infection or Intestinal Tuberculosis: Rapid Discrimination by Targeted Next-Generation Sequencing

Abstract

We read with interest the study by Ye et al. [1]. The authors demonstrated that targeted next-generation sequencing (tNGS) has high sensitivity (83%) and 100% specificity for detecting Mycobacterium tuberculosis from fresh ulcer base biopsy samples, offering an alternative to conventional methods like acid-fast bacillus staining, TB-PCR, and histopathological examination. Given the diagnostic challenges in tuberculosis-endemic regions, this represents a potentially significant advancement in clinical gastroenterology.

The novelty of the study represents promising findings, but there are limitations.

First, the study was restricted to patients with positive Interferon Gamma Release Assay (IGRA) results. Since IGRA can yield false-negative results, especially in immunocompromised patients, this selection criterion may have excluded some patients with intestinal tuberculosis (ITB), thereby limiting generalizability [2].

Second, the test missed 17% of true ITB cases. The authors attributed this to a low bacterial load in biopsy samples. However, particular patient-based factors such as immune suppression, prior antibiotic use, and variation in granuloma formation might also have played a role in the lower detection rate.

Third, the study was performed at a single institution and the sample size was small. These restrict the generalisability of the results as the specificity and sensitivity of a diagnosis may vary with respect to population, healthcare setting and endemic region. These factors may significantly influence the performance of tNGS, including variation of TB strain types, host immune responses and healthcare infrastructure. To establish such results prior to impulsive concretising of clinical use, a multicentre validation study with diverse patient cohorts and under diverse laboratory conditions would be necessary.

Although tNGS performs better than some conventional tests, the absence of the gold standard of TB culture limits direct comparison [3]. Its real-life benefits are unknown without head-to-head assessments against diagnostics such as Xpert MTB/RIF (Xpert M. tuberculosis/rifampicin) assay, a nucleic acid amplification test endorsed by the World Health Organization for detecting M. tuberculosis complex and resistance to rifampicin in under 2 h [4]. Moreover, histopathological data would be nullable, if based on biopsies performed on ulcer bases, which are very much subject to sampling error given the variable distribution of pathogens and difficulties in obtaining fresh tissue. Additional studies are needed to investigate whether larger numbers of biopsy sites or broader approaches to molecular techniques would increase sensitivity and feasibility.

In summary, while Ye et al. have provided meaningful insights into the potential of tNGS for rapidly distinguishing ITB from Crohn's disease with latent tuberculosis infection, the approach requires further validation. Addressing issues such as patient selection bias, low sensitivity in a subset of cases, single centre limitations, and the lack of head-to-head comparisons with established diagnostic tools will be crucial. Future multicentre studies involving larger and more diverse patient cohorts, along with investigations into optimised sampling strategies, are necessary to fully establish the clinical utility and impact of tNGS in routine practice.