Short summary

Traditional biomarkers are unable to predict who will progress from latent tuberculosis infection (LTBI) to active tuberculosis (TB). The hypothesis is that the addition of microRNA profiles, cyto- and chemokines to established risk markers will make it possible to identify those with LTBI who will progress to TB. We hope that this addition to already known risk factors for progresserion can create a toll to allow phisicians to treat only patients with high risk of progression to active TB. 

Rationale

Tuberculosis (TB) remains a major global health problem and ranks worldwide as the leading cause of death (1.6 million) among infectious diseases with 10 million new cases in 2017. One-fourth of the world population is estimated to be infected with Mycobacterium tuberculosis and about 10% with latent tuberculosis infection (LTBI) will eventually develop active TB. Based on a recent review, 2-5% with LTBI will progress to active TB disease within 2 years. Certain host related risk factors have been identified with respect to progression from LTBI to active disease, such as ¬¬young age, male sex, immigrant from high TB burden countries and immunocompromised disease such as HIV. Knowledge about the entire pathophysiological mechanism for progression is still incomplete. To reduce the incidence of TB, treatment of LTBI is essential; but treatment of LTBI needs to be well targeted and individualized. Currently, we do not have any laboratory or clinical test to accurately identify the 10% of the individuals with LTBI who will progress to active TB. The tuberculin skin test and the interferon gamma release assays (IGRA) can be used to identify people with LTBI. While both assays have a high negative predictive value by identifying persons not having LTBI, they are poor predictors for the risk of developing TB. Furthermore, as announced in "The World Health Organization End TB Strategy" in low-incidence countries in 2014, management of LTBI in high-risk groups is one of the priority actions in its proposed program for TB elimination. 

During the last decades, many researchers have tried to identify biomarkers that can provide information about TB and progression from LTBI to TB. Despite substantial efforts the results have been few and the use of conventional biomarkers has so far failed. Nevertheless, the introduction of novel types of biomarkers: microRNAs (miRNAs) and whole blood RNA expression have provided some promising results. miRNAs are a group of single-stranded (18-to 25-nucleotides) non-coding RNA molecules that regulate gene expression by causing translation blockade or mRNA cleavage. Regarding TB, miRNAs could be a turning point for the use of biomarkers. It is well-established that interferon-? and tumor necrosis factor-? play a major role in the protection against TB and in the control of LTBI. Recent studies indicate that specific miRNA signatures may differentiate between TB and LTBI. Use of host RNA expression in whole blood helped distinguish TB from other diseases in African children and helped to identify people at risk of developing active TB. To date, no miRNAs have been discovered which can identify persons with LTBI who will progress to active disease.

AIMS:

1. To identify prognostic circulating miRNA as biomarkers for progression from LTBI to TB

2. To develop a novel TB progression risk profile based on the identified prognostic miRNAs, cytokines, chemokines and quantitative IGRAs 

3. To provide novel insight into the risk of progression from LTBI to active infection using a new TB 

progression risk profile

4. To discover new pathophysiological mechanisms in TB progression and disease localization based on the identified prognostic miRNAs, cytokines, chemokines and quantitative IGRAs 

Hypotheses:

1. miRNAs can differentiate LTBI from TB free individuals

2. The link between disease progression from LTBI to active TB can be tracked by miRNAs

3. Variation in miRNAs between progressors and non-progressors will facilitate the development of 

a TB progression risk profile that can predict who will develop TB

4. An interplay between host-related phenotypic and genotypic characteristics combined with 

bacterial genotypic characteristics can explain why some with LTBI progress to TB. Reasons for different localizations of TB may also be explained by this interplay.

Description of the cohort

In this study we intend to use blood samples from adult patients newly diagnosed with LTBI. LTBI will be diagnosed by a positive IGRA and absence of active TB disease. Definition of TB will be either culture verified by isolation of M. tuberculosis or by clinical and radiologic characteristics evaluated by the treating specialists in accordance with the national guidelines.

Individuals with LTBI will be eligible for preliminary inclusion if:

 i)  At high risk of recent transmission based on TB contact tracing investigations, 

ii)  Newly converted to a positive IGRA test, 

iii)  Newly arrived asylum seeker from high TB incidence areas. 

Exclusion Criteria

i) Children (below 18 years) 

ii) Patients with known immunodeficiency whom requires immediate treatment for LTBI (HIV, Biologic treatment, organ transplantation)

Data and biological material

Blood samples and clinical data from patient charts 

Collaborating researchers and departments

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital. 

• Assistant Professor, MSc., PhD, Søren Feddersen

Department of  Department of Clinical Immunology, Odense University Hospital. 

• Speciality Registrar, ph.d., Associate professor, Kristian Assing

Department of Respiratory Medicine, Odense University Hospital. 

• Senior consultant, Associate professor, Ingrid Louise Titlestad

Department of Infectious Diseases, Aarhus University Hospital

• Ass. professor, Ph.D. Christian Wejse

Department of Medicine, Vejle Hospital, Hospital Lillebælt

• Professor, DMSc. Ole Hilberg

Researcher, Odense University Hospital and Clinical Institute, University of Southern Denmark

• MD, MPH, PhD, Stephanie Bjerrum. 

Department of Infectious Diseases, the University Hospital Herlev Gentofte 

• Senior Consultant, Pernille Ravn

Center for Clinical Epidemiology, Odense University Hospital. 

• Ass. Professor, senior veterinarian, clinical epidemiologist PhD, Kim Oren Gradel. 

Head Molecular and Experimental Mycobacteriology Group, Nat. Reference Center for Mycobacteria, Borstel Germany

• Professor. Dr., Stefan Niemann