**6. Existing research gaps**

#### **6.1. Research needs**

Tracing of MDR TB contacts is important to prevent TB disease and further transmission. Priority studies needed include those to identify the most effective contact-tracing procedures for close contacts and the most effective follow-up procedures in healthcare workers constantly exposed to MDR TB. As part of the management of MDR TB contacts, studies on specific groups are needed, for example on children below the age of five years, children with HIV infection and other immunocompromised states. In particular, studies are needed: 1) for treated contacts: (randomised) clinical trials: 2) to determine which drugs and which drug combina‐ tions and dosages are optimal for preventive therapy; 3) to determine the duration of preven‐ tive therapy; 4) to assess the effectiveness of preventive therapy in conjunction with antiretroviral treatment; 5) to assess the risk of development of new drug resistance in contacts receiving (inadequate and adequate) preventive therapy; 6) for untreated contacts, and healthcare workers constantly exposed to MDR TB: 7) to identify the optimal follow-up period for different groups of individuals; and 8) to identify the optimal frequency of testing for LTBI during the follow-up period.

In order to increase adherence to treatment of MDR/XDR TB contacts (and reduce the risk of development of new drug resistance in contacts), studies are needed: 1) to identify new drugs with less adverse events and to explore possible (positive and negative) interactions between combined drugs; 2) to identify biomarkers indicating the risk of progression from LTBI to TB disease and 3) to assess operational management to shorten preventive therapy. Since the provision of preventive therapy has economic and logistic implications at the national and community level, cost-effectiveness and cost-benefit studies are also needed. These studies are particularly valuable because they can help to inform the decision on intervention policies..

A substantial amount of funding has been injected into research on various aspects of TB but there are still many issues that require additional research especially in the area of childhood tuberculosis. The most salient ones include:1) accurately quantifying the global burden of childhood tuberculosis especially in the endemic areas; 2) improving the understanding of the disease interactions with the immune system and re-evaluating the role of BCG and the new vaccine candidates in protecting children and adults against TB; 3) defining the diagnostic contribution of novel T-cell–based assays in endemic and non-endemic areas especially with regard to diagnosis of paediatric tuberculosis; 4) identifying new ways of diagnosing child‐ hood tuberculosis in HIV negative and in TB/HIV co-infection in children, particularly in resource-limited settings; 5) carrying out operational research aimed at improving the access of children in endemic areas to preventive therapy and treatment, using the existing DOTS/ DOTS Plus frameworks; 6) evaluating the efficacy of new short-course intermittent preventive chemotherapy regimens especially those aimed at childhood TB; 7) exploring shorter durations of treatment in immune-competent children with smear-negative disease; 8) defining the optimal treatment regimen and treatment duration in children with TB/HIV co-infection; 9) monitoring the impact of MDR and XDR tuberculosis on children and evaluating regimens for effective MDR/XDR disease prevention and treatment; 10) developing and evaluating new drugs that may shorten the treatment duration and/or assist with the treatment of MDR/XDR disease and emphasizing case finding and reporting as some of the strategies to combat the escalation of XDR-TB [http://ec.europa.eu/research/research-eu].

#### **6.2. Need for more specific diagnostic tests**

TBVAC and Muvapred, where valuable progress has been achieved. Several other candidates are still in the pre-clinical phase. For example, mutation of virulence genes produced a TB strain potentially conferring greater protection with fewer side effects than BCG. In addition, an improved, recombinant BCG vaccine with a higher efficacy and a better safety profile

New research is directed at the development of a multistage TB vaccine containing latency antigens, an attractive concept, which is actively being pursued (Andersen, 2007). Such a vaccine could be used as a booster vaccine with the goal of preventing new infections in those uninfected with MTB and to prevent reactivation in those with LTBI. Unfortunately, the lack of reliable correlates of protective immunity currently remains a major obstacle to predict

Tracing of MDR TB contacts is important to prevent TB disease and further transmission. Priority studies needed include those to identify the most effective contact-tracing procedures for close contacts and the most effective follow-up procedures in healthcare workers constantly exposed to MDR TB. As part of the management of MDR TB contacts, studies on specific groups are needed, for example on children below the age of five years, children with HIV infection and other immunocompromised states. In particular, studies are needed: 1) for treated contacts: (randomised) clinical trials: 2) to determine which drugs and which drug combina‐ tions and dosages are optimal for preventive therapy; 3) to determine the duration of preven‐ tive therapy; 4) to assess the effectiveness of preventive therapy in conjunction with antiretroviral treatment; 5) to assess the risk of development of new drug resistance in contacts receiving (inadequate and adequate) preventive therapy; 6) for untreated contacts, and healthcare workers constantly exposed to MDR TB: 7) to identify the optimal follow-up period for different groups of individuals; and 8) to identify the optimal frequency of testing for LTBI

In order to increase adherence to treatment of MDR/XDR TB contacts (and reduce the risk of development of new drug resistance in contacts), studies are needed: 1) to identify new drugs with less adverse events and to explore possible (positive and negative) interactions between combined drugs; 2) to identify biomarkers indicating the risk of progression from LTBI to TB disease and 3) to assess operational management to shorten preventive therapy. Since the provision of preventive therapy has economic and logistic implications at the national and community level, cost-effectiveness and cost-benefit studies are also needed. These studies are particularly valuable because they can help to inform the decision on intervention policies..

A substantial amount of funding has been injected into research on various aspects of TB but there are still many issues that require additional research especially in the area of childhood tuberculosis. The most salient ones include:1) accurately quantifying the global burden of

moving into phase I clinical trials is a possible prospect.

414 Tuberculosis - Current Issues in Diagnosis and Management

**6. Existing research gaps**

during the follow-up period.

**6.1. Research needs**

vaccine efficacy in all TB vaccine trials for both adults and children.

In the field of diagnosis, there is an urgent need to replace sputum microscopy the current gold standard test, with more sensitive tests that are applicable at point of care. Despite the fact that the technique can only pick up 60% of cases, it has been in use for over a hundred years. Furthermore, sputum culture is not suitable for extrapulmonary TB and for paediatric TB since children can not produce sputum. On the other hand, the newer immunological based tests such as IGRAs are not well suited for use in TB/HIV co-infection and in high burden TB areas, where they cannot be accurately used to distinguish active from latent TB. Since the majority of the infected people never actually develop the disease, there is need to have a diagnostic tool which is able to distinguish latent from active disease and help to identify healthy individuals from diseased ones. Improved diagnostics are critical to TB care and control.

The need for serious investment in the critical areas especially in new TB diagnostic tools, drug susceptibility testing, and development of new biomarkers to enable health providers detect TB disease activity and to determine follow up treatment outcomes cannot be over emphasised. The fact that a number of new diagnostic tools are in the pipeline, including culture-based tests to identify M. tuberculosis and those used to determine drug resistance based on molecular assays and immune response is good news. However, there is still need to ensure that the new tests can be availed world-wide and be used at the point-of-care even in resource-poor settings, where there may be limited technical expertise and the necessary equipment. [http://ec.euro‐ pa.eu/research/research-eu]

#### **6.3. Newer biomarkers for TB disease activity, cure and relapse**

There are three major reasons that can be used to justify the need for new TB biomarkers : 1) a diagnostic test which is able to differentiate between healthy individuals with a latent TB infection and patients with active dsease is needed; 2) a prognostic test which can be able to predict the risk of latent TB becoming active needs to be established; 3) there is need for a diagnostic test that can be used to serve as a surrogate endpoint of disease which can be used for monitoring drug and vaccine trials in TB. It is envisaged that the basis for these novel diagnostic measures will be biomics, comprising metabolomic, proteomic and transcriptomic profiles in custom-made biosignature. Identification of non invasive biomarkers, especially the molecular assay of M. tuberculosi fragments in urine and the measurement of volatile biomarkers of volatile organic compounds generated by Mycobacteria TB in the breath or the oxidative stress resulting from infection is one step in the right direction. [http://ec.europa.eu/ research/research-eu]

**7. Future prospects**

**7.1. Reducing the burden of childhood tuberculosis**

[http://www. ec.europa.eu/research/research-eu].

and utility for HIV-infected individuals, particularly children.

**7.2. Involvement of funders and industry**

**7.3. Back to basic research**

TB in children presents a number of difficult challenges which will only be solved by a shift in research priorities. Advances in paediatric TB research will provide wider insights and opportunities for TB control. While development of a new vaccine to prevent TB should be the ultimate goal, development of better diagnostics represent one of the most important steps towards improving individual case management and also providing a more robust case definition for much needed drug and vaccine trials for studies on TB epidemiology and correlates of protective immunity in childhood. Data on the epidemiology of childhood TB may in turn help to inform public health policy by providing a window on current transmission and the effectiveness of control strategies and by identifying children with LTBI for chemo‐ prophylaxis to limit the future propagation of the epidemic. Emphasis should be placed on reducing the vulnerability of the community because successful control of the tuberculosis epidemic is the most effective way to reduce the burden of childhood tuberculosis However, this will require a holistic approach with sustainable poverty alleviation as a key element

Peadiatric Tuberculosis: Is the World Doing Enough?

http://dx.doi.org/10.5772/54953

417

Important resources are required for the exploration of pathways leading to TB diagnosticsoriented basic science in pathogen biology, biomarker discovery, systems biology and point of care test development. The current priorities for TB vaccine development are: i) new vaccine candidates that achieve sterile eradication, and that can progress into phase II and phase III trials; ii) vaccine testing in a naïve stage on M. tuberculosis uninfected individuals; iii) vaccines which can achieve post-exposure prophylaxis to those who are already infected (currently 2 billion people); iv) strategies on how to get vaccines from the research bench to the bedside and into the community. Apart from the protective effect of novel vaccine candidates, priority should be given also to their delivery route, formulation (storage, shelf-life and distribution)

As we talk about nano technology and pin point delivery of drugs it is a shame that 130 years after the Robert Koch's discovery of M. Tuberculosis we still have huge gaps in our under‐ standing of the biology, immunology and pathophysiology of the bacillus. We are, as yet, not able to explain fully the molecular, biochemical and immunological mechanisms that enable TB infection to go on for years and cause severe disease and death. With the availability of state-of-the-art molecular research tools such as functional genomics and metabolomics a paradigm shift towards empahsising basic research could help provide answers to some of the unanswered questions about M.tuberculosis in general, and paediatric TB in particular. The currently available knowledge has proved insufficient when it comes to the rational design of vaccines or other control tools and this has resulted in a lot of trial-and-error approaches. With

#### **6.4. Need for post-exposure vaccines and those effective against all M. tuberculosis strains**

The Bacille Calmette-Guerin (BCG) vaccine is currently the only vaccine in use against tuberculosis. The efficacy of this vaccine is limited to prevention of severe forms of tuberculosis among children and there are lots of problems in cases of TB/ HIV coinfection.The current vaccine candidates are being developed for pre-exposure administration but, considering the fact that one third of the world's population is already infected, there is a serious need for a post-exposure vaccine to prevent re-activation. Another shortcoming with the vaccines in the pipeline is that they can delay clinical TB but cannot achieve sterile eradication. There is need for combination vaccines that can combine the effects of booster vaccines with another generation of vaccines that can act to effect sterilisation at the post-exposure stage. Focus should also be put on the development of a vaccine that can afford protection against the wide range of M. tuberculosis strains, to ensure universal effectiveness.To avoid complications in clinical and epidemiological research, the evaluation of all the vaccines should also deal with confounding factors such as prior BCG vaccination or HIV status and there should be well worked out guidelines for use of these vaccines in children [http//www.ec.europa.eu/research/ research-eu]

#### **6.5. Development of new drugs**

When it comes to the current status of clinical, diagnostic and therapeutic strategies, childhood TB has been grossly neglected and there is, therefore need for better and standardized treatment strategy. Although there is a reasonable number of candidates in the discovery and pre-clinical pipeline, there are still gaps between the different stages of TB drug development, and drugs specically targeting paediatric TB are still needed. Most of the drugs in the pipeline use the same mechanisms with the majority aimed at boosting efficacy or shortening the duration, with very few targeingt dormant stages of the bacillus and, therefore, not suitable for eradication of latent infections. Thus urgency for serious research into the development of new drugs and treatment regimens aimed at achieving this therapeutic objective cannot be over emphasised. Dealing with TB/HIV co-infection is another gap that needs serious attention: there is need to develop drugs that can prevent dormant mycobacteria from re-activating in HIV-positive individuals [http://ec.europa.eu/research/research-eu.
