Improving the Outcomes of Children With Tuberculosis Through Innovative Diagnostics and Treatment Monitoring

NCT ID: NCT06815588

Last Updated: 2025-02-07

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-09-15
• Study Completion Date: 2026-03-30

Brief Summary

This study aims at identifying and evaluating novel diagnostic methods for children evaluated for respiratory tuberculosis. The investigators will use alternative samples like stool, urine, and masks to diagnose children with respiratory tuberculosis. Once diagnosed, the investigators will use target next generation sequencing to determine if the bacillus is resistant to any of the drugs used for treatment. Additionally, children initiated under TB treatment will be followed-up during treatment to measure blood biomarkers for outcome prediction. Finally, spirometry will be performed longitudinally until 3 months after the end of treatment to assess the lung capacity of children treated for respiratory TB. All children initiated on TB treatment will fill in a quality of life questionnaire.

Detailed Description

Tuberculosis (TB) remains a significant global health concern, particularly among children, who are especially vulnerable, with an estimated 1.25 million incident cases and 214,000 deaths reported in 2022. TB in children presents unique challenges due to its subtle clinical manifestations and paucibacillary nature, often resulting in difficulties in diagnosis. Compared to estimated incidence, only 49% children were diagnosed and reported, with the highest proportion of under-reporting taking place in children under 5 years - of 58%. Gaps and challenges persist in accurately diagnosing and treating TB in children, stemming from limitations in traditional diagnostic methods, like sputum culture, that often lack sensitivity and specificity in children. Therefore, there is a pressing need to identify new diagnostic techniques that are both accurate and feasible in pediatric settings.

In recent years, researchers have explored innovative approaches, including the utilization of alternative sample types such as mask samples, urine, or stool, for TB diagnosis in children. These alternative samples offer potential advantages in terms of ease of collection and potentially improved diagnostic accuracy. In 2021, the World Health Organization (WHO) recommended stool as an alternative sample for TB diagnosis in children with signs and symptoms of TB, since stool is non-invasive and easy to collect even in young children. A recent systematic review showed that Xpert Ultra summary sensitivity verified by culture was 56.1% (95% CI 39.1 to 71.7), and specificity was 98.0% (95% CI 93.3 to 99.4), nevertheless the sensitivity results are highlighted as "moderate quality evidence", therefore more research is needed on the performance of this alternative sample in children for the diagnosis of tuberculosis. Moreover, the lipoarabinomannan (LAM) found in the membrane of the Mycobacterium tuberculosis bacillus can be identified in urine and pilot data generated by our group shows a sensitivity of 66% in adults with culture-confirmed pulmonary tuberculosis. This urine-based assay can be critically useful in the diagnosis of extrapulmonary TB as it's not sputum-based. In addition to stool and urine, another promising sample can be obtained through a gelatin strip inside a mask worn by children with presumptive TB. The exhaled breath potentially containing M. tuberculosis bacilli is then captured on the gelatin filter, processed, and tested using GeneXpert.

Once the tuberculosis diagnosis is made, an important challenge lies in drug susceptibility testing (DST), in case of multi-drug resistant TB or rifampicin-resistant TB (MDR/RR-TB)(6). The standard of care for DST is sputum culture, which has many challenges in children, as highlighted above. Targeted next-generation sequencing (tNGS) has emerged as a promising tool for assessing drug sensitivity, providing valuable insights into personalized treatment regimens for pediatric TB cases. In addition, tNGS can be performed on clinical samples like sputum or stool with the potential of a rapidly-available result informing the choice of regimen and clinical decision-making.

After treatment initiation, a main concern lies in treatment monitoring, this step being especially challenging in children. Transcriptomics holds promise for monitoring treatment response in children with TB. By examining gene expression patterns, transcriptomic analyses can offer valuable insights into the efficacy of treatment regimens and help identify early indicators of treatment failure or relapse. Both WHO definitions and TBnet definitions will be used to assess TB outcomes.

Understanding and assessing the burden of post-TB sequelae in children is crucial for ensuring comprehensive care and addressing long-term health outcomes. Therefore, studying and evaluating port-TB disease in children is imperative for improving clinical management strategies and enhancing the overall health outcomes of pediatric TB patients. Spirometry will be used to assess pulmonary function in children.

This study aims to research a novel and comprehensive approach to TB diagnosis, treatment adaptation, and treatment monitoring in the pediatric population, with the overall goal of improving TB outcomes in children.

Aims and objectives

Aim: Improve the diagnosis of tuberculosis and treatment outcomes in children evaluated for tuberculosis

Specific objectives:

1. Identify the diagnostic accuracy of mask strip samples against a composite reference standard for the diagnosis of respiratory tuberculosis in children.

2. Determine the diagnostic accuracy of a novel urinary LAM assay against a composite reference standard for the diagnosis of respiratory tuberculosis in children.

3. Evaluate the diagnostic accuracy of stool and perform targeted next generation sequencing from stool for drug sensitivity testing.

4. Assess the utility of a transcriptomic signature for treatment monitoring and treatment shortening in children treated for respiratory tuberculosis.

5. Measure the pulmonary function changes in children diagnosed with respiratory tuberculosis using spirometry.

6. Assess the quality of life of children treated for respiratory tuberculosis at baseline, during, and after treatment.

Conditions

Tuberculosis

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Eligibility Criteria

Inclusion Criteria

• Children under 15 years evaluated for respiratory TB.
• Signature of the informed consent form by the parent/guardian and assent form by the child if applicable.

Exclusion Criteria

• Refusal to sign informed consent

• Minimum Eligible Age: 0 Years
• Maximum Eligible Age: 14 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

LMU Klinikum

OTHER

Sponsor Role: collaborator

Research Center Borstel

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christoph Lange, Professor

Role: PRINCIPAL_INVESTIGATOR

Research Center Borstel

Locations

Marius Nasta Institute of Pneumology

Bucharest, BUC, Romania

Site Status: RECRUITING

Countries

Romania

Central Contacts

Anca Vasiliu, MD, PhD

Role: CONTACT

avasiliu@fz-borstel.de

+33652727749

Dragos Baiceanu, MD

Role: CONTACT

dragos_baiceanu@yahoo.com

Facility Contacts

Dragos Baiceanu, MD

Role: primary

dragos_baiceanu@yahoo.com

+40749574412

Other Identifiers

EESS - RoGer Pedi

Identifier Type: -

Identifier Source: org_study_id