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अखिल भारतीय आयुर्विज्ञान संस्थान, नई दिल्ली
All India Institute Of Medical Sciences, New Delhi

Dr U B Singh

Dr. Urvashi B Singh MD PhD

 Professor,

Chief, Tuberculosis Section Department of Microbiology

AIIMS, New Delhi-110029

Telephone: +91-11-26596436 Mob. Tel.: +91-9811120203

Fax:+91-11-26588663 Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

Executive Summary

Tuberculosis (TB) remains a major public health problem despite being curable. Of 1.8 billion people infected with Mycobacterium tuberculosis the world over (one-third of the world population), 20% are in India. India accounts for more than 2 million of the 8 million new cases each year (25%) and 500,000 deaths/year of the 2 million deaths (25%) all over the world. The emergence of AIDS, the decline of socioeconomic standards, and the overburdened health facilities have contributed to the resurgence of TB in the country. Control of TB is further compounded by the rising incidence of drug resistance and, particularly, the emergence of multidrug-resistant TB.

In Delhi more than 40% population of the 15 million people residing are infected with M. tuberculosis. There are 39,600 new cases annually, of which 17,100 are infectious, with 95 new smear positive cases /lac population every year. . Nearly 108 people develop TB every day. More than four people develop TB every hour. There are 220 new cases/lac every year.

We in the department cater to over 20,000 patients annually.11, 000 patients are given service for microscopy and culture. Three to four thousand patients are given PCR diagnosis especially for extra-pulmonary tuberculosis. Another three to four thousand patients are given rapid culture service. Sensitivity to first line and second line anti-tubercular drugs is offered for 1500 to 2000 patients. With the demand for better services in tuberculosis rapid diagnosis and resistance detection increasing steadily, we are continuing to introduce the latest technology for patient services. We are now buying the rapid detection system for drug resistance detection, which can help us report drug resistance in a matter of 2 hours.

Significant clinical research in Tuberculosis has been carried out in the Tuberculosis laboratory, under Dr Urvashi B Singh. The research work has provided lead information on epidemiology and prevalence of sensitive as well as drug resistant tuberculosis in India. Also research has unraveled the mutations leading to rifampicin resistance in the multidrug resistant M. tuberculosis isolates prevalent in our country. This data has been further used to generate a novel, rapid and economical method for detection of rifampicin resistance in cultures as well as on new and old slides. These in-depth studies have thus lead to the application of bench work to bedside diagnostics resulting in a renaissance for rapid diagnosis of drug resistant tuberculosis.

These lead studies have applied importance and are of immediate relevance from the public health point of view in our country. Most of the work is published in prestigious high impact peer reviewed international and national journals of Infectious diseases and tuberculosis and are summarized below.

  1. RESEARCH APPLICATIONS

    1. UNDERSTANDING THE EPIDEMIOLOGY AND PATHOGENESIS OF TUBERCULOSIS IN INDIA.

      Each year, 9 million new cases of tuberculosis (TB) are recorded, of which 2 million result in fatality. Diagnostics, chemotherapy and vaccination are available; however, the disease is far from being eradicated.

      Genotyping of clinical isolates in different parts of the world has shown that global epidemiology of TB is propagated by thousands of different genotypes. Limited epidemiological studies have been done in India in the past. We attempted to highlight predominant spoligotypes responsible for transmission and prevalence of disease in the Delhi region (Singh et al., Emerg Inf. Dis., 2004). The study was further extended to other geographical regions of India to cover areas from the North and the South, with the aim to study the genetic diversity of M. tuberculosis isolates present in different geographical regions of India, their predominance and impact on the disease transmission. This was the first study that included large number of samples from five different geographical regions of India representing North and South and depicted that different M.tuberculosis genotypes are prevalent in different regions of India. The study defined the phylogenetic clades of M. tuberculosis in India versus rest of the world for the first time. The clades obtained were further analyzed as ‘‘ancient’’ and ‘‘modern’’ lineages of tubercle bacillus. The study concluded that different parts of India also differed with regard to predominant spoligotypes, underlining the differences in the introduction and evolution of TB in India, the East-African-Indian (EAI) clade being more commonly found in Southern parts and the (Central-Asian) CAS clade being more predominant in the North (Singh et al., Infect. Genet. Evol. 2007). The group went on to study the association between host and pathogen populations and concluded that the association remains strong despite social exchange and travel. The study depicted that the EAI lineage is well established in India and that CAS appears to be emerging or more recently introduced to India. The study also reflected on the association of these two clades to ongoing transmission. The ancestral EAI strains seemed to be less often associated with drug resistance as compared to the evolutionarily younger CAS clade. The association of drug resistance with this prevalent clade will have implications on TB control in North India. These findings are important for making public health strategies, control programs and evolutionary biology. (Arora, J., et al., Infect. Genet. Evol., 2009). This work has triggered a number of studies in India and abroad (Please see the citation of the work).

    2. MOLECULAR INSIGHTS INTO SPREAD OF MULTIDRUG RESISTANT TUBERCULOSIS IN INDIA.

      The emergence of anti-tuberculosis drug-resistance, especially multidrug-resistant tuberculosis {MDR TB, resistance at least to isoniazid (INH) and rifampicin (RIF)}, poses a serious threat to the success of TB control programs The true magnitude of the problem of antituberculosis drug-resistance worldwide is not known. India has the largest number of TB cases in the world, the knowledge of development and spread of drug resistant clones is important in guiding TB control strategies. The simultaneous rapid detection of the type of mutation conferring resistance and the genotype would reflect on the extent of MDR TB transmission and hence the tuberculosis control in the community.

      Rifampicin resistance serves as a surrogate marker for the detection of MDRTB, since more than 95% Rifampicin resistant isolates are also INH-resistant. The group designed a study to identify Rifampicin resistance mutations in MDRTB strains collected from five different geographical regions in India. The study also aimed to obtain an initial assessment of the spread of dominant spoligotypes of M. tuberculosis and their role in the MDR TB transmission in India, as well as to verify if the MDR TB cases in India were resulting from inadequate treatment within historical clones of tubercle bacilli, or among recently imported clones of ‘‘modern’’ bacilli. The study showed the spread of three predominant spoligotypes that were endemic in India, contributing to the MDRTB transmission in the country, clearly refuting the association of specific spoligotypes with drug resistance. This was the first study of its kind in a large number of M. tuberculosis isolates.( N. Suresh et al., Infect. Genet. Evol. 2006).

    3. DESIGNING OF NOVEL RAPID DETECTION METHOD FOR MULTIDRUG RESISTANT TUBERCULOSIS.

      Drug resistance in tuberculosis is a significant problem in countries endemic for tuberculosis. A sensitive, specific, and high-throughput reverse line blot assay (RLBA) for the detection of genotypic resistance to rifampicin (RIF) was designed and evaluated. The assay based on reverse hybridization principle simultaneously detects 13 different mutations affecting 6 independent codons. Application of the method to a panel of 292 MDR TB isolates and susceptible strains from 5 different cities in India showed 98% concordance with the sequencing results. This rapid, simple, economical, and highly sensitive assay provides a practical alternative to sequencing for genotypic evaluation of RIF resistance in Mycobacterium tuberculosis. (N. Suresh et al., Diagnostic Microbiology and Infectious Disease 2006).The assay was designed based on sequencing data generated by the group in Indian strains and has a positive predictive value for drug resistance of >99%;while commercial kits developed in Europe miss out 28%-30% of Indian MDR isolates.

    4. RAPID DETECTION OF RIFAMPICIN RESISTANCE AND SPOLIGOTYPES FROM STAINED SPUTUM SMEARS.

      Microscopy is the mainstay of laboratory diagnosis of tuberculosis especially in resource poor countries and under DOTS. Using DNA extracts from Ziehl–Neelsen (ZN)-stained sputum smears, a single-tube nested polymerase chain reaction was optimized to confirm Mycobacterium tuberculosis complex and detect rifampin (RIF) resistance by sequencing, The results obtained were concordant with the 1% proportion method and DNA sequencing performed on culture isolates. (N. Suresh et al. Diagnostic Microbiology and Infectious Disease 2007). Spoligotyping done on DNA extracted from old slides may have application in identification of spoligotypes in control programme implemented areas remote from research laboratory and would also increase our knowledge about the clonal structure of Mycobacterium tuberculosis in the population and hence reflect on the efficacy of the programme.(N. Suresh et al., Journal of Microbiological Methods 2006).This pioneering work in addition could pave the way for early diagnosis, resistance detection ,disease transmission and treatment. The work is relevant not only for Indians, but also in global context.

    5. CONTRIBUTIONS TO INTERNATIONAL SPOLIGOTYPING DATABASE

      The group has contributed significant amount of data to the international spoligotyping database to reflect on the Indian strains and their transmission vis a vis global strains of tuberculosis. In the joint publication, ( Brudey et al;BMC Microbiology 2006) an updated SpolDB4 version, which contains 1939 STs representing a total of 39,295 clinical isolates originating from 122 countries was published .SpolDB4 is representative of a total of 141 countries. The SpolDB4 provides a higher resolution picture of the worldwide M.tuberculosis genome diversity assessed by spoligotyping.

    6. HIV-TB CO-INFECTION

      Worldwide TB is the most common co-infection in subjects infected with HIV-1. In contrast to other HIV-1 associated opportunistic infections, TB may occur at any level of immunodeficiency, and has been clearly shown to be associated with enhanced HIV-1 morbidity and mortality. Recent studies have elucidated the basis of HIV-1 induction by MTB. Additionally, mononuclear cells from subjects with TB are activated, and more susceptible to a productive infection by HIV-1. Tuberculosis accelerates the course of HIV infection through various mechanisms. M. tuberculosis infection results in cytokine dysregulation and significantly increases the levels of secreted cytokines such TNF-α and MCP-1 in infected cells, thereby promoting HIV replication and genetic diversity. Immune activation resulting from the presence of TB may affect the surface expression of coreceptors by uninfected mononuclear cells, thereby modulating their susceptibility to HIV-1 infection. MTB is associated with upregulation of CCR5 expression on peripheral blood mononuclear cells in vivo. Co-infection with HIV inhibits cell-mediated responses to MTB through interruption of IL-2 signaling. Under these conditions the risk of acquiring MTB infections from the environment, progression to disease, or re-activation of a latent TB infection may occur rapidly. An ongoing study is looking at theIntracellular cytokine staining to study T lymphocyte turnover by CFSE based proliferation assay and the cytokines IL-1, IL-2, IL-6, TNF-α, IFN-γ; Surface staining to study the markers: CD4, CD8, CD3, CD45RA, CD45RO, CD57, CD71, HLA-DR, CD38, CCR5, CXCR4, FoxP3, CD25 and HIV-1 Viral Load quantification in a cohort of HIV-TB co-infected individuals.

    7. SEQUENCES SUBMITTED TO GENBANK.

      Genbank SubmissionS: Urvashi B.Singh et al: Genbank accession numbers

      Tuberculosis: 176 sequences M. tuberculosis rpoB gene sequences submitted and accession nos. obtained from the Genbank. Delhi-AY308002-AY308015, AY271363-AY271377, AY280838-AY280807, AY800556, Lucknow-AY793001-AY793019, AY280841-AY280846, Pune-AY800520-AY800555, Chennai-AY800505-AY800477, Trivandrum-AY800506-AY800519.

  2. CLINICAL WORK

    1. TB CO-INFECTIONS AND CO-MORBIDITIES & OTHER MYCOBACTERIAL DISEASES

      Diagnostic service to HIV-TB co-infected patients is very helpful in treatment initiation and follow-up. NTM may be responsible for a significant proportion of mycobacterial infections in HIV sero-positive individuals. Despite the high endemicity of tuberculosis in developing countries like India, the presence of NTM should be ruled out; especially in immuno-compromised HIV sero-positive individuals before instituting anti-tubercular therapy empirically. In addition, non-response of NTM to ATT may be wrongly attributed to multi-drug resistant tuberculosis. Khatter et al , Indian J Tuberc 2008;55:28-33;

      An effort to study the response of these patients to intermittent DOTS regimen under the Revised National Tuberculosis Control Program is ongoing. Research is ongoing to compare daily and intermittent regimens. (Please see Ongoing Projects).

      Research projects to define the role of Vitamin D and Zinc Supplementation to Tuberculosis patients in improving time to smear conversion in Cat I treatment group under the RNTCP (In collaboration with DR R Goswami,Department of Endocrinology and Prof S K Sharma, HOD, Medicine, Ongoing Projects).

      An ongoing project entitled, ‘Detection of Mycobacterial pathogens in patients with Crohn’s disease’ in collaboration with Dr Govind Makharia, Department of Gastroenterology, is trying to define the role of Mycobacterium avium paratuberculosis in Crohn’s disease.

    2. PAEDIATRIC TUBERCULOSIS

      An ongoing effort at early diagnosis and treatment in Pediatric patients is in place. Diagnostic services in these patients are very helpful in instituting early treatment.

      Das et al, Annals of Tropical Paediatrics (2008) 28, 137–141;

      Menon et al, J of Tropical Pediatrics, Nov. 2010

    3. MOLECULAR DIAGNOSTICS TO AID CLINICAL DIAGNOSIS AND TREATMENT.

      The group has published extensively utilizing their expertise in molecular diagnostics of tuberculosis in various clinical samples.

      Sen et al Diagnostic Cytopathology 2003,, Vol 28, No 2

      Bhanu et al, Journal of Medical Microbiology (2005), 54, 1–5;

      Singh et al Am. J. Trop. Med. Hyg., 75(5), 2006, pp. 960–963;

      Das et al, Annals of Tropical Paediatrics (2008) 28, 137–141;

      Khatter et al , Indian J Tuberc 2008;55:28-33;

      Nag et al Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 25, No 2 (February), 2009: pp 131-136

      Makharia et al Indian J Gastroenterol 2009(September–October):28(5):165–168

      Makharia et al Am J Gastroenterol 2010; 105:642–651;

    1. Research Capacity (Lab Capacity)

      Diagnosis: Laboratory diagnosis on pulmonary and extra-pulmonary has been streamlined and is communicated to clinicians with the following time lines:

      1. Smear (using ZN technique) within 24 hrs
      2. Using rapid culture methods (MGIT 960 and Bactec 460), the positive culture grows within 7-10 days, though the negative need incubation for 7 weeks.
      3. Anti-tubercular sensitivity to all first line and second line drugs is reported within 4-6 days of culture growth.

      Research

      Research Projects: 13 collaborative research projects with clinical departments.

      Two PhD students are working on the following research topics:

      1. "Identification & Evaluation of Biomarker in Various Clinical Samples from Tuberculosis Patients & Comparative Analysis with other Diagnostic Methods”.
      2. "Molecular Epidemiology of Extensively Drug Resistant TB (XDR-TB) and Development of a Rapid Diagnostic Technique.

        Original Research: Design and development of ‘Rapid Diagnostic Technique for Drug Resistant Tuberculosis’.

    2. Ongoing Research Projects

       

      Sl No.Title of ProjectFunding Agency
      1 Co-PI Role of oral vitamin D as an adjunct therapy in Category I Pulmonary Tuberculosis along With assessment of immunological parameters DBT, Deptt. of Science, Govt. of India
      2 Co-I Efficacy and safety of immnuomodulator (Mycobacterium w) as an adjuvant therapy in Category II and multi-drug resistant pulmonary tuberculosis along with reduction in the duration of therapy and to study immunological parameters. Department of Biotechnology, Ministry of Science & Technology, Government of India and Cadila Pharmaceuticals Ltd.: Principal Investigator & National Coordinator
      3 Co-I Efficacy of thrice weekly intermittent short course antituberculosis chemotherapy in tuberculosis patients with and without HIV infection National AIDS Control Organization (NACO); Ministry of Health and Family Welfare; Govt. of India
      4 Co-I Treatment outcome and drug resistance among CAT II pulmonary tuberculosis under Revised National TB Control Programme (RNTCP) of India Revised National TB Control Programme NCT of Delhi
      5 Co-I Efficacy and safety of immunomodulator Mw as an adjunct therapy in Cateogry I (new sputum smear positive) pulmonary tuberculosis, along with assessment of immunological parameters (Double-blind, Randomized, Placebo-Controlled, Multicentre Clinical Trial) Department of Biotechnology, Ministry of Science & Technology, Government of India
      6 Co-I Evaluation of the efficacy of thrice weekly DOTS regimen in TB pleural effusion at six months (multicenter project) with Department of Medicine National AIDS Control Organization (NACO); Ministry of Health and Family Welfare; Govt. of India
      7 Co-I Efficacy of oral zinc administration as an adjunct therapy in Category I Pulmonary Tuberculosis along with assessment of immunological parameters (Double-blind, Randomized, Placebo-Controlled, Multicenter Clinical Trial) Department of Biotechnology, Ministry of Science & Technology, Government of India
      8 Co-I Detection of mycobacterial pathogens in Crohn’s disease patients with Department of Gastroentrology and Human Nutrition. Department of Biotechnology, Ministry of Science & Technology, Government of India
      9 Co-I Diagnosis of genital tuberculosis in infertile women and the effect of antitubercular therapy with Department of Obstetrics and Gynaecology Indian Council of Medical Research
      10 Co-I Microscopy Center for Directly Observed, (DOTS) Therapy, Short-Course with Department of Medicine, Ministry of Health, Govt. of India  
      11 Co-I A study on treatment of Genital Tuberculosis-Randomized Controlled Trial of either discontinuation at 6 months or continuation till 9 months after initial response to 6 months RNTCP category I treatment with Department of Obstetrics and Gynaecology Ministry Of Health
      12 Co-I To study the diagnostic value of Quantiferon Gold Test in detecting latent TB infectionin End stage Renal Disease patients on Renal Replacement therapy. ICMR

       

      Completed Research Projects

      Co- Investigator

       
      Surveillance of anti tuberculosis drug resistance. Indian Council of Medical Research
      Principal Investigator Agency
      Typing of M.tuberculosis by Restriction Fragment Length Polymorphism (RFLP) using 32P-labelled IS6110 Probes. International Atomic Energy Agency, Vienna
      Co- Investigator  
      Surveillance of anti tuberculosis drug resistance. Indian Council of Medical Research
      Investigation of risk factors and transmission of drug resistant tuberculosis(in collaboration with Department of Medicine) INCLEN, USA
      Microscopy Center for Directly Observed, (DOTS) Therapy, Short-Course(in collaboration with Department of Medicine) Ministry of Health,

      Govt. of India

      The research work of the group has provided

      1. Novel data regarding prevalent tuberculosis strains in the country, their routes of entry and association with local population.
      2. Data on mutations responsible for rifampicin resistance and multidrug resistant tuberculosis in India.
      3. Generation of a novel, rapid and economical test for early and accurate detection of multidrug resistant tuberculosis
      4. Novel method for diagnosing drug resistance and genotypes from microscopic slides.
      5. New perspectives in the correct diagnosis and treatment of tuberculosis.
      6. Effort is ongoing to define HIV-TB interplay.

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