Stephanus Malherbe and colleagues conducted positron emission tomography–computerized tomography lung scans of patients before and after tuberculosis therapy and report that even in cured, culture-negative patients the majority show lung lesions after 6 months of therapy, suggesting possible persistence of Mycobacterium tuberculosis infection. The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET–CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET–CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.

Background User-friendly, rapid, inexpensive yet accurate TB diagnostic tools are urgently needed at points of care in resource-limited settings. We investigated host biomarkers detected in serum samples obtained from adults with signs and symptoms suggestive of TB at primary healthcare clinics in five African countries (Malawi, Namibia, South Africa, The Gambia and Uganda), for the diagnosis of TB disease. Methods We prospectively enrolled individuals presenting with symptoms warranting investigation for pulmonary TB, prior to assessment for TB disease. We evaluated 22 host protein biomarkers in stored serum samples using a multiplex cytokine platform. Using a pre-established diagnostic algorithm comprising of laboratory, clinical and radiological findings, participants were classified as either definite TB, probable TB, questionable TB status or non-pulmonary TB. Results Of the 716 participants enrolled, 185 were definite and 29 were probable TB cases, 6 had questionable TB disease status, whereas 487 had no evidence of TB. A seven-marker biosignature of C reactive protein, transthyretin, IFN-γ, complement factor H, apolipoprotein-A1, inducible protein 10 and serum amyloid A identified on a training sample set (n=491), diagnosed TB disease in the test set (n=210) with sensitivity of 93.8% (95% CI 84.0% to 98.0%), specificity of 73.3% (95% CI 65.2% to 80.1%), and positive and negative predictive values of 60.6% (95% CI 50.3% to 70.1%) and 96.4% (95% CI 90.5% to 98.8%), respectively, regardless of HIV infection status or study site. Conclusions We have identified a seven-marker host serum protein biosignature for the diagnosis of TB disease irrespective of HIV infection status or ethnicity in Africa. These results hold promise for the development of a field-friendly point-of-care screening test for pulmonary TB.

Rationale: Inadequacy of T-cell responses may result in the development of tuberculosis (TB). Myeloid-derived suppressor cells (MDSCs) have been described as suppressors of T-cell function in cancer biology and recently in several infectious diseases. Objectives: To explore the presence and role of MDSCs in TB. Methods: We analyzed surface markers of MDSCs in peripheral blood and at the site of disease in TB cases and in patients with lung cancer, and in peripheral blood of asymptomatic tuberculin skin test–positive individuals with recent (household) or remote exposure to Mycobacterium tuberculosis (M.tb) and in uninfected healthy control subjects. To evaluate the suppressive capacity of MDSCs, cells of household contacts infected with M.tb and TB cases were isolated and cocultured with CD3+ T cells. Measurements and Main Results: Our results demonstrate an increased presence of MDSCs after recent M.tb infection and disease. We confirm their suppression of CD4+ T-cell function, including reduced cytokine responses and inhibition of CD4+ T-cell proliferation. Only MDSCs from TB cases reduced T-cell activation, altered T-cell trafficking, and suppressed CD8+ T-cell functions. M.tb-expanded MDSCs were associated with significantly higher IL-1β, IL-6, IL-8, granulocyte colony–stimulating factor, and monocyte chemotactic protein-1, and reduced granulocyte-macrophage colony–stimulating factor and macrophage inflammatory protein-1 beta levels in coculture. Conclusions: These data reveal that innate MDSCs are induced not only during active TB at similar levels as found in cancer, but also in healthy individuals after recent exposure to M.tb. These cells diminish protective T-cell responses and may contribute to the inability of hosts to eradicate the infection and add to the subsequent development of TB disease.

Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinantMycobacterium bovisbacillus Calmette-Guérin (BCG) vaccine previously shown to be safe and immunogenic in adults, was evaluated for safety in its intended target population, namely, newborn infants in a region with high prevalence of tuberculosis. A total of 48 newborns were vaccinated intradermally with VPM1002 (n= 36) or BCG Danish strain (n= 12) in a phase II open-labeled, randomized trial with a 6-month follow-up period. Clinical and laboratory measures of safety were evaluated during this time. In addition, vaccine-induced immune responses to mycobacteria were analyzed in whole-blood stimulation and proliferation assays. The safety parameters and immunogenicity were comparable in the two groups. Both vaccines induced interleukin-17 (IL-17) responses; however, VPM1002 vaccination led to an increase of CD8⁺IL-17⁺T cells at the week 16 and month 6 time points. The incidence of abscess formation was lower for VPM1002 than for BCG. We conclude that VPM1002 is a safe, well-tolerated, and immunogenic vaccine in newborn infants, confirming results from previous trials in adults. These results strongly support further evaluation of the safety and efficacy of this vaccination in larger studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01479972.)

Identification of novel host biomarkers in plasma as candidates for the immunodiagnosis of tuberculosis disease and monitoring of tuberculosis treatment response

Tuberculosis (TB) is a global health problem, with c. 2 billion people infected worldwide. Of these, 3–10% will progress to active TB disease, resulting in almost 9 million cases and 1.5 million deaths per year [ 1 x 1 WHO Global Tuberculosis Report 2012. WHO fact sheet number 104. Available at: http://www.who.int/tb/publications/factsheet_global.pdf. ((last accessed 29 March 2013).) Google Scholar See all References 1 ]. Infection with human immunodeficiency virus (HIV) is the most potent known risk factor for progression to TB: patients with HIV are more likely to progress directly to active disease or reactivate latent TB infection (LTBI) than immunocompetent individuals [ 1 x 1 WHO Global Tuberculosis Report 2012. WHO fact sheet number 104. Available at: http://www.who.int/tb/publications/factsheet_global.pdf. ((last accessed 29 March 2013).) Google Scholar See all References , 2 x 2 Nunn, P, Williams, B, Floyd, K et al. Tuberculosis control in the era of HIV. Nat Rev Immunol. 2005; 5: 819–826 Crossref | PubMed | Scopus (177) | Google Scholar See all References ].