Current Respiratory Medicine Reviews - Volume 9, Issue 3, 2013

Although Mycobacterium tuberculosis infection remains a global killer, many immunopathological aspects of the disease are poorly understood, and defence mechanisms long thought to help host defences such as granuloma formation have recently been challenged. This review highlights contemporary evidence that granulomas may benefit mycobacterial survival and dissemination, particularly citing the zebrafish model of pathogenesis. Other selected examples of novel research covered include the role of the lung extracellular matrix, mycobacterial evasion techniques, chemokine response, immune reconstitution in the context of human immunodeficiency virus, and biomarker development. These advances may yield improved diagnostics and offer targets for anti-tuberculous chemotherapy and vaccine development.

There is robust epidemiological evidence that susceptibility to tuberculosis is in part heritable. This has driven the use of genetics to try to find the genes and pathways involved that could in the longer term contribute towards the development of new therapies and a better vaccine for this major global health problem. This paper reviews the progress made in the field to date, and discusses the challenges inherent in undertaking genetics studies on a complex disease with clinically diverse phenotypes, that affects many genetically different populations and which is further complicated by the presence of a pathogen which has a genome too.

The environment can contribute to a person’s susceptibility to tuberculosis, with a number of factors increasing the risk of developing active disease. In this chapter, we shall examine the evidence for an association between TB and nutrition, smoking, alcohol, intestinal parasite infection, and the newer anti-TNF immunosuppressive drugs. For further in depth information, readers are guided towards reviews on individual topics where available. Concurrent disease, other immunosuppressive medication and HIV infection have been covered elsewhere.

Development of a vaccine with enhanced efficacy compared to that of the Bacillus Calmette Guerin (BCG) vaccine is essential to reduce the global TB burden. This is challenging since an effective vaccine will need to induce protection that surpasses that induced by natural infection with M. tuberculosis and currently there are no identified biomarkers of protection. Nonetheless progress has been made over the last 20 years in the development and clinical evaluation of novel TB vaccines, evidenced by 15 candidate vaccines being tested in phase I clinical trials and 4 reaching phase IIb and III trials. In order to make further progress there is a need to further understanding of the interactions between M. tuberculosis and its host and for the development of ongoing partnerships to facilitate the design, harmonisation and funding of clinical trials.

In this review we will give an overview of current diagnostics tools excluding GeneXpert which will be described elsewhere. We will focus on interesting advances in smear and culture methods alongside the application of immunological assays such as antibody tests and interferon-gamma release assays. Mention will be made of recently developed assays such as those for antigen-detection using urine as well as possible future directions of diagnostic development.

Xpert MTB/RIF is an automated real-time polymerase chain reaction test for simultaneous detection of tuberculosis and rifampicin resistance. Xpert MTB/RIF has demonstrated excellent accuracy in clinical evaluation studies, but has reduced sensitivity for detection of smear-negative tuberculosis. Since sample processing and detection are largely automated, Xpert MTB/RIF is potentially suitable for implementation in resource-limited settings. There are, however, a number of practical constraints to the use of Xpert at the point-of-care. Xpert remains a relatively costly test, and clear demonstration of cost-effectiveness will be needed to support efforts to scale up testing in high burden countries.

The optimal time to initiate antiretroviral therapy (ART) in patients presenting with HIV-associated tuberculosis has been a controversial issue. Early initiation of ART may be complicated by high pill burden, overlapping drug toxicities, and an increased risk of immune reconstitution inflammatory syndrome. Delayed initiation of ART may result in progressive immune decline, HIV-associated complications and death. Retrospective studies of HIV/TB coinfected patients suggested that initiation of ART during TB treatment might be beneficial. Emerging evidence from recent randomised controlled trials supports early ART initiation in HIV/TB patients with advanced immunosuppression, apart from those presenting with tuberculous meningitis. However, current guidelines for antiretroviral therapy vary in their recommendations for timing of ART initiation in HIV-associated TB.

The current treatment regimen against drug susceptible tuberculosis (DS-TB) was defined by the 1980s. Since then the emergence of the global HIV pandemic and the escalation of drug resistant (DR-) forms of TB have presented new challenges for therapeutic research. Priority goals include shortening DS-TB treatment, improving DR-TB treatment and making combined TB-HIV therapy easier. To help achieve these goals, a range of new drugs and treatment strategies are currently being evaluated. Phase IIb and III clinical trials are ongoing to assess combinations involving the high-dose rifamycins, the 8-methoxyquinolones, a diarylquinoline (bedaquiline) and the nitroimidazoles. Other compounds (e.g. novel oxazolidinones and ethylenediamines) are at earlier stages of clinical development. Overall, there are grounds for optimism that recent advances will contribute towards achievement of new treatment regimens in the foreseeable future. However, long-term investment, political commitment and scientific endeavour are crucial to ensure that progress is sustained and the benefits of recent advances reach those in the greatest need.

Concerns are increasing that the drugs we have used to treat this chronic pulmonary infection will cease to work because of development of resistance, raising the threat of untreatable disease. This review explains the molecular and clinical basis of resistance. The current best practice for the treatment of multi-drug resistance is described. There are a number of new drugs and regimens currently under investigation and these are described. The importance of improved case finding, diagnosis and early treatment are emphasised.

Nocturia is a common symptom in the elderly and is associated with sleep fragmentation, irregular heartbeats, diabetes and stroke. It may be associated with obstructive sleep apnea-Hypopnea syndrome (OSAHS), and when present is seen more often in patients less than 50 years of age. OSAHS is often overlooked as a cause of nocturia, especially in the presence of coexisting diseases such as diabetes. OSAHS patients with frequent nocturia have higher body mass index (BMI), greater apnea-hypopnea index (AHI), and worse quality of life. Nocturia is correlated with the severity of OSAHS and the use of continuous positive airway pressure (CPAP) has shown to be beneficial. In this review, we discuss the various pathophysiologic mechanisms, clinical features and treatment options for patients with nocturia and obstructive sleep apnea-Hypopnea Syndrome.