Pre- and Post-treatment Lung Microbiota, Metabolome and Immune Signatures at the Site of Disease in Patients With Active Pulmonary Tuberculosis

NCT04700579 | Recruiting

• 1 other identifier: N19/09/126
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 3

Brief Summary

The diverse microbial communities in different parts of the human body (microbiome) are important for health but understudied in pulmonary tuberculosis (TB), which is the single biggest infectious cause of death in the world. The investigators will study the site-of-disease microbiome (in the lung bronchoalveolar space) in TB cases to investigate how, before TB treatment, metabolic compounds made by microbes affect host biomarkers important for TB control. The investigators will ask this question again at the end-of-treatment and one year later. Specifically, the investigators will sample the lung at the active TB hotspot identified by imaging and compare this to a non-involved lung segment usually in the opposite lung. The investigators will compare the lung microbiome to other sites in the body (i.e. oral cavity, nasopharynx, supraglottis, and gut). A small amount of blood (\~15 ml) will be collected to assess peripheral immunological correlates of the host microbiome. Protected specimen brushings of the lung will be used to explore transcriptomic signatures and how these relate to the lung microbiome. The investigators will also apply these questions to the same number of controls (healthy patients and patients with an alternative diagnoses). This will lay the foundation for clinical trials to evaluate if specific bacteria have diagnostic (e.g., PCR) or therapeutic potential (e.g., antibiotics, prebiotics, probiotics, vaccines) where targeting the microbiome could improve clinical outcomes.

Conditions

TB - Tuberculosis; HIV/AIDS

Keywords

Microbiome; Short Chain Fatty Acids; Immunological Biomarkers

Outcome Measures

Primary Outcomes (3)

• Characterization of changes in microbiota in diseased vs. non-diseased lung segments, stratified by HIV status.

  Lung microbiome in diseased and non-diseased segments determined by 16S rRNA gene sequencing.

  Up to 18 months

• Association of specific microbial taxa in diseased segments with elevated SCFAs and impaired host inflammation and tissue repair biomarkers.

  Correlation analysis of specific cytokines profiled using commercial multiplexed Luminex panels and SCFAs measured using Gas chromatography-mass spectrometry (GC-MS) assays.

  Up to 18 months

• Evaluate the impact of treatment on the lung microbiome.

  Characterize bacterial community resilience alongside changes in microbial and host biomarkers.

  Up to 18 months

Study Arms (3)

TB Cases

* n= 50 (25 HIV positive and 25 HIV negative) * Xpert MTB/RIF Ultra-confirmed TB

Healthy Household Contacts

* n= (25 HIV positive and 25 HIV negative) * Culture negative TB result

Sick controls

* n=50 * Diseases: Asthma, Chronic obstructive pulmonary disease (COPD), Cancer, Bronchiectasis (including post-TB) and Pneumonia

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Self-presenting patients with Xpert MTB/RIF Ultra-confirmed TB (n=50, equally stratified by HIV) and culture negative HHCs (n=50, equally stratified by HIV) will be recruited from primary care clinics (Scottsdene and Wallacedene) in Cape Town, South Africa. An additional 50 sick controls with other lung diseases will be referred from Tygerberg Academic Hospital.

You may qualify if:

• years old.
• Agree to undergo CXR and/or CT scan.
• Has unilateral TB disease defined as one lung with extensive evidence of TB disease (non-applicable to healthy controls; sick controls will require an alternative diagnosis).
• No evidence of prior TB treatment and/or CXR/CT does not have obvious evidence of prior TB.
• Willing to undergo a research bronchoscopy at baseline, 6 months and 18 months and likely to remain in the area for the study period.
• If HIV-positive, must be stable on antiretroviral therapy (ART) for ≥1 year.
• Able and willing to return for follow-up visits, with no plans to move in the near future.
• Willing to comply with study requirements i.e. provision of contact details and written, informed consent prior to enrolment.

You may not qualify if:

• Less than 18 years or older than 60 years of age.
• Has already initiated TB treatment.
• Rifampicin resistant.
• Has a previous history of TB.
• Bilateral TB disease defined as both lungs with extensive TB disease
• Has received probiotics, antibiotics or inhaled steroids within three months prior to enrolment (not applicable to sick controls)
• Has diabetes mellitus, which affects TB disease, treatment response, and the microbiome
• Has a contraindication for bronchoscopy (e.g., FEV1 \<70%), as determined by bronchoscopists according to best practice guidelines
• Has a daily alcohol intake of more than 6 beers or 4 mixed drinks
• Is pregnant (a commercial human chorionic gonadotropin determination assay will be performed in accordance with manufacturer's guidance on urine) or pregnancy planned for follow-up period
• Recent hospitalization for any reason

Sponsors & Collaborators

• University of Stellenbosch: lead
• New York University: collaborator

Study Sites (3)

Kraaifontein Community Health Centre

Cape Town, Western Cape, 7570, South Africa

RECRUITING

Scottsdene Clinic

Cape Town, Western Cape, 7570, South Africa

RECRUITING

Wallacedene Clinic

Cape Town, Western Cape, 7570, South Africa

RECRUITING

Related Publications (12)

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  PMID: 22699611 BACKGROUND

• Wade WG. The oral microbiome in health and disease. Pharmacol Res. 2013 Mar;69(1):137-43. doi: 10.1016/j.phrs.2012.11.006. Epub 2012 Nov 28.

  PMID: 23201354 BACKGROUND

• Weiner J 3rd, Parida SK, Maertzdorf J, Black GF, Repsilber D, Telaar A, Mohney RP, Arndt-Sullivan C, Ganoza CA, Fae KC, Walzl G, Kaufmann SH. Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients. PLoS One. 2012;7(7):e40221. doi: 10.1371/journal.pone.0040221. Epub 2012 Jul 23.

  PMID: 22844400 BACKGROUND

• Grice EA, Kong HH, Renaud G, Young AC; NISC Comparative Sequencing Program; Bouffard GG, Blakesley RW, Wolfsberg TG, Turner ML, Segre JA. A diversity profile of the human skin microbiota. Genome Res. 2008 Jul;18(7):1043-50. doi: 10.1101/gr.075549.107. Epub 2008 May 23.

  PMID: 18502944 BACKGROUND

• Shenoy MK, Iwai S, Lin DL, Worodria W, Ayakaka I, Byanyima P, Kaswabuli S, Fong S, Stone S, Chang E, Davis JL, Faruqi AA, Segal MR, Huang L, Lynch SV. Immune Response and Mortality Risk Relate to Distinct Lung Microbiomes in Patients with HIV and Pneumonia. Am J Respir Crit Care Med. 2017 Jan 1;195(1):104-114. doi: 10.1164/rccm.201603-0523OC.

  PMID: 27447987 BACKGROUND

• Wipperman MF, Fitzgerald DW, Juste MAJ, Taur Y, Namasivayam S, Sher A, Bean JM, Bucci V, Glickman MS. Antibiotic treatment for Tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed. Sci Rep. 2017 Sep 7;7(1):10767. doi: 10.1038/s41598-017-10346-6.

  PMID: 28883399 BACKGROUND

• Botero LE, Delgado-Serrano L, Cepeda ML, Bustos JR, Anzola JM, Del Portillo P, Robledo J, Zambrano MM. Respiratory tract clinical sample selection for microbiota analysis in patients with pulmonary tuberculosis. Microbiome. 2014 Aug 25;2:29. doi: 10.1186/2049-2618-2-29. eCollection 2014.

  PMID: 25225609 BACKGROUND

• Cheung MK, Lam WY, Fung WY, Law PT, Au CH, Nong W, Kam KM, Kwan HS, Tsui SK. Sputum microbiota in tuberculosis as revealed by 16S rRNA pyrosequencing. PLoS One. 2013;8(1):e54574. doi: 10.1371/journal.pone.0054574. Epub 2013 Jan 24.

  PMID: 23365674 BACKGROUND

• Cui Z, Zhou Y, Li H, Zhang Y, Zhang S, Tang S, Guo X. Complex sputum microbial composition in patients with pulmonary tuberculosis. BMC Microbiol. 2012 Nov 23;12:276. doi: 10.1186/1471-2180-12-276.

  PMID: 23176186 BACKGROUND

• Segal LN, Clemente JC, Tsay JC, Koralov SB, Keller BC, Wu BG, Li Y, Shen N, Ghedin E, Morris A, Diaz P, Huang L, Wikoff WR, Ubeda C, Artacho A, Rom WN, Sterman DH, Collman RG, Blaser MJ, Weiden MD. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat Microbiol. 2016 Apr 4;1:16031. doi: 10.1038/nmicrobiol.2016.31.

  PMID: 27572644 BACKGROUND

• Segal LN, Alekseyenko AV, Clemente JC, Kulkarni R, Wu B, Gao Z, Chen H, Berger KI, Goldring RM, Rom WN, Blaser MJ, Weiden MD. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome. 2013 Jul 1;1(1):19. doi: 10.1186/2049-2618-1-19.

  PMID: 24450871 BACKGROUND

• Naidoo CC, Nyawo GR, Wu BG, Walzl G, Warren RM, Segal LN, Theron G. The microbiome and tuberculosis: state of the art, potential applications, and defining the clinical research agenda. Lancet Respir Med. 2019 Oct;7(10):892-906. doi: 10.1016/S2213-2600(18)30501-0. Epub 2019 Mar 22.

  PMID: 30910543 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Bronchoalveolar lavage fluid, Protected specimen brushings, Sputum, Oro- Nasopharyngeal swabs, Urine, Blood and Stool.

MeSH Terms

Conditions

Latent Tuberculosis; Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Grant Theron, PhD

  University of Stellenbosch

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Grant Theron, PhD

CONTACT

(+27) 021 938 9693; gtheron@sun.ac.za

Charissa Naidoo, PhD

CONTACT

(+27) 0219389955; ccnaidoo@sun.ac.za

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 18 Months
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 28, 2020
• First Posted: January 8, 2021
• Study Start: March 4, 2021
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: May 6, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: The data will be available once the findings are published.
• Access Criteria: Data access will be granted to interested collaborators and parties through sharing of data files or login information for the study's secure RedCap electronic database during the course of patient recruitment.

Locations

ZA (3)