Imaging latent tuberculosis infection with radiolabeled nitroimidazoles.

In a previous paper, an overview of the use of PET/CT in the management of tuberculosis (TB) was provided and the potential role of nitroimidazole imaging in LTBI was considered [1]. During latent TB, dormant bacilli putatively reside in a hypoxic environment of caseating lung granulomas. Exposure of Mycobacterium tuberculosis (Mtb) to progressive hypoxia in vitro induces a dormant state characterized by reduced replication and metabolism analogous to that postulated for bacilli in LTBI. In vitro, Mtb has been shown to enter microaerophilic nonreplicating persistent (NRP) stage 1, if the dissolved oxygen content falls below 1 %. NRP stage 1 is characterized by thickening of the outer cell wall of Mtb and termination of DNA synthesis. If the oxygen content further drops to approximately 0.06 %, the bacilli enter NRP stage 2, which is accompanied by reduced susceptibility to standard antiTB drugs but increased susceptibility to nitroimidazole drugs [2]. In light of this, metronidazole, an antimicrobial agent active against anaerobic bacteria, has been investigated as a possible therapy for TB, particularly latent and persistent TB. Metronidazole has recently been documented to be a viable option for treatment of multidrugresistant (MDR) TB [3]. Oxygen is an essential nutrient for mammalian cells, because of its role as the terminal acceptor in oxidative phosphorylation. When tissues are gradually deprived by oxygen over time, the cells adapt to the new physiological state of insufficient oxygen by upregulation and transcription of certain proteins to meet metabolic demands. This phenomenon is called hypoxia and it may occur in diseases such as stroke, myocardial infarction with sudden vascular occlusion or as a consequence of poor perfusion, e.g., in diabetic limbs, arthritic joints or infections such as tuberculosis. Clearly, the ability to identify hypoxia has implications in a wide range of medical conditions. A clinically suitable method for detection of hypoxia is thus essential. In oncology, invasive probe-based methods have been previously used including the Eppendorf needle electrode and optical needle probes such as OxyLite. Alternatively, immunohistochemical methods have been applied to detect markers of hypoxia in biopsy samples taken from patients. These markers include both exogenous systemically delivered probes that are administered to the patient, localizing hypoxic regions, and are detected by antibody techniques in tissue specimens, as well as endogenous proteins that are overexpressed under hypoxic conditions. However, the invasiveness of these procedures as well as their susceptibility to sampling error has encouraged the development of image-based methods for detecting and quantifying hypoxia [4]. PET probes have been used to investigate hypoxia in cancer extensively. There is adequate evidence to show that Mtb is exposed to hypoxia in the granuloma in latent TB [5]. It can therefore be envisaged that hypoxic granuloma in TB and in anaerobic and microaerophilic infections could be detected by PET probes for hypoxia imaging. The heterogeneous lesions both in active disease and subclinical disease could be studied by combined PET/CT imaging. The CT component & Alfred O. Ankrah [email protected]