Romania Tuberculosis Portal

Tuberculosis in Romania – Major public health problem – project context

Tuberculosis (TB) is a major public health threat in Romania. The recent escalation of the occurrence of the disease has been complicated due to the appearance and development of multi-drug resistant tuberculosis (MDR TB) or extensively drug-resistant tuberculosis (XDR TB). The ability for the Romania and worldwide community of TB researchers to understand the nature of the TB disease will be greatly improved by using a common database containing patients’ medical images, treatment information, lab work, and clinical data. This common database can facilitate adherence to the treatment protocol as well as serve as a consistent repository of records of the treatment regime for particular histories of disease.

According to the ECDC Tuberculosis surveillance and monitoring in Europe 2016, in 2014, 58.008 cases of TB were reported in 29 EU/EEA countries (Table 3). As in previous years, three countries (Poland, Romania and the United Kingdom) accounted for approximately 50% of all reported cases, with Romania alone accounting for 27.4% of all cases. However, the TB global incidence in Romania, after a peak in 2002 has constantly declined as shown in the graph below.

TB global incidence in Romania – 2016 – National TB Program

According to the same source quoted above, similar to 2012 and 2013, country-specific notification rates in 2014 differed more than 30-fold, ranging from 2.5 in Iceland to 79.7 per 100.000 in Romania, marking a steady, substantial decrease with rates declining by 6−8% per year.

However, despite the success in managing drug-susceptible TB, drug-resistant tuberculosis is a major challenge to the effectiveness of National Tuberculosis Program in Romania, placing the country in the list of the 18 high-burden countries for MDR-TB in the WHO European Region. Compared to other countries in this region of WHO this incidence is low and Romania is not being considered as an MDR-TB hot spot. The proportion of MDR-TB tuberculosis was in 2012 of 4.23% in new TB cases and 10.7% in relapsed cases. Nonetheless, the incidence of MDR-TB is maintaining in the recent years and we can note a decrease in the percentage in new TB cases (in 2013, 2.8% MDR-TB in new cases and 11% in retreatment cases) according to the WHO Tuberculosis country profiles, 2012, 2013.

Patients registered with MDR Pulmonary TB in 2016 – National Tuberculosis Program

Currently, the treatment for the MDR TB patients is covered from the following funding sources respectively, the Global Fund to Fight AIDS, Tuberculosis and Malaria in Romania (2%) and Norwegian Funds (24.6%), the remaining treatment being covered by national sources through the NTP.

The development of MDR- and XDR-TB is the result of a number of mutational events which lead to the formation of resistance to TB drugs. Resistance to TB drugs provides a significant resilience and increases M. tuberculosis survival. Full genome sequencing of various forms of MDR-TB and XDR-TB is essential, as the presence of expected sequence diversity in M. tuberculosis would provide a basis for understanding pathogenesis, immune mechanisms, and bacterial evolution. Studying these molecular mechanisms and outlining region – specific differences is extremely important both for Romania health programs and to support worldwide efforts to combat the disease.

The goal of the project is to develop the Romania TB Portal to facilitate research aimed at diagnosis and treatment of drug-resistant tuberculosis. The clinical images of lungs (CT and X-ray) will be used for development of computational methods of TB diagnosis. Clinical data will be collected and stored in Portal’s database for computer-aided analysis of factors contributing to the development of the disease. Connection of Portal’s metadata with the original clinical samples collection (clinical lab samples taken from TB patients) would allow researchers to establish various cohorts for subsequent partial or full-genome sequencing of Romanian TB strains. Analysis of genomes of Romanian TB strains would allow for improved analysis of epidemiological situation in Romania, and forming informed opinion about required drug regiments and efficiency of diagnosis with common microbiological tools.

The Romania TB Portal will store anonymized medical images, lab work, treatment information and clinical data from the Romanian TB patients and use user interface developed for Romania Portal. The Romania TB Portal will utilize the software developed previously for the other countries and populate it with the anonymized data from the participating Romanian TB patients including medical images, lab work, treatment information and clinical data.  Information submitted into the Portal will be appropriately de-identified and authorized for upload by the Romanian researchers ensuring compliance with the appropriate Romanian laws and regulations.

Project Summary

Title: “Romania Tuberculosis Portal”
CRDF Project No.: 61135/62294
Starting Date: March 11, 2015
Duration: September 10, 2016

Objectives

The goal of the project is to establish a new public health resource for TB in Romania and to create open access information resources on tuberculosis (TB) in Romania.

      • Establish a sustainable ongoing clinical database for the Romania TB public health program based on both new data acquired from incoming patients (medical images and other clinical data) as well as extracting data from existing medical records and histories of interest.
      • Establish a comprehensive large scale clinical portal for TB researchers worldwide by making the de-identified data available via Internet.
      • Extract the initial set of M. tb strains isolated from TB patients residing in various regions of Romania. The strain selection strategies shall be determined after full review of optimal methods. Selected strains shall be sequenced and analyzed using the corresponding genomes for unique markers and SNPs associated with known drug resistance.
      • Comparative sequence analysis of genes and genomic markers from these genomes will contribute to understanding of local strains of Mycobacterium tuberculosis and hopefully suggest possible novel diagnostics, therapies and drug combination

Our ultimate goal is to perform comparative analysis of all existing TB genomes, find SNPs and find correlations of genome variations with a) patients’ medical history, and b) resistance of corresponding bacteria to known drugs. For annotation purposes, we will map sequenced reads to the M. tuberculosis reference genome (H37Rv). We will search for variants with high association to the MDR and XDR phenotypes, as well as resistance to specific drugs using the clinical and in vitro data available for these samples. We will also look for genetic variability of pathogen for distinct socio-economic and geographic groups.

Besides the genomic objectives, the project team will search for correlations between genomic data and clinical data (clinical picture, imagistic peculiarities, treatment response and treatment outcome).

Expected Outcome

The results of this project will be unique because:

– Multiple XDR and MDR Mtb genomes from Romania samples have never been sequenced before.

Besides the genetic information, the work in this project will result in a collection of additional clinical data and metadata that describes patients’ history, symptoms, radiologic findings which will allow making correlations between drug resistance profile, dynamics of TB genome mutations, patient’s response to treatment and treatment outcome.

This multi-country project will also allow to:

    • Further investigate differences between genomes of TB strains with varied virulence, clinical manifestation of disease, resistance to drugs;
    • Reveal phylogenetic/phylogeographic peculiarities of Mtb strains in Romania;
    • Perform comparative analysis of MDR- and XDR-TB strains from Romania with strains of tuberculosisH37Rv, M. tuberculosis CDC1551 and strains from other countries;
    • Add to the existing body of information and knowledge to promote research resulting in creating new generation of TB drugs, vaccines, and diagnostic methods.

The sequencing of M. tuberculosis strains will be part of a larger project, The Romanian TB Portal, which itself integrates in a multi-country database project, alongside the Belarus and Georgia TB portals and possible other joining countries in the future. This involves, besides collecting samples for genome sequencing, also the analysis of several clinical, radiological, socio-economic and medical data (history, treatment response, etc), with the objective to search for correlations between these data and the genetic profile of the strains.

Partners

“Marius Nasta” Pneumophtisiology Institute of Bucharest is one of the oldest hospitals in Romania. It started as Filaret Hospital, the first tuberculosis hospital in Romania.

Since 1997, the “Marius Nasta” Pneumophtisiology Institute coordinates the National Program for Tuberculosis Control in line with the World Health Organization recommendations. The institute is currently providing guidelines for tuberculosis control in Romania and guides the activity of generations of specialists in the field of pneumology.

“Marius Nasta” Pneumo-phtisiology Institute is also one of the institutions that implement programs for TB prevention and control financed by the Global Fund to Fight AIDS, Tuberculosis and Malaria in Romania and Norwegian Funds.

The project is developed in partnership with the United States National Institute of Allergy and Infectious Diseases (NIAID) and Office of Cyber Infrastructure & Computational Biology and Forschungszentrum Borstel, Germany through the Molecular Mycobacteriology Group, the National Reference Center for Mycobacteria

Status

The project is midway as of early July 2016, enrollment of patients and corresponding data collection reaching half of the target.

Participants

National Institute of Allergy and Infectious Diseases (NIAID)
Office of Cyber Infrastructure & Computational Biology
5601 Fishers Lane
Rockville, MD 20850 USA
Telephone: (301) 496-8219
Fax: (301)-480-0784

“Marius Nasta” Pneumophtisiology Institute 
Viilor, sector 5, 050159
Bucharest, Romania

Forschungszentrum Borstel
Molecular Mycobacteriology Group
National Reference Center for Mycobacteria
Parkallee 1
23845 Borstel, Germany