Update in Tuberculosis and Nontuberculous ... - ATS Journals

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Apr 15, 2014 - The Journal published two clinical studies in 2013 of patients in the United States with nontuberculous mycobacterial (NTM) lung disease.
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE Update in Tuberculosis and Nontuberculous Mycobacterial Infections 2013 Randall Reves1,2 and Neil W. Schluger3,4 1

Department of Medicine, University of Colorado, Denver, Colorado; 2Denver Public Health Department, Denver, Colorado; 3Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York; and 4Departments of Epidemiology and Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York

The past year saw incremental progress rather than dramatic breakthroughs in mycobacterial disease research. Research in nontuberculous mycobacteria published in the Journal focused on host factors that may underlie or predispose to infection. Tuberculosis (TB) research touched on epidemiology, basic immunology, diagnostics, and clinical trials, as well as murine studies of antibiotic regimens. Researchers from the University of California, San Francisco added to their impressive 20-year body of work with a description of the molecular epidemiology of TB in immigrant communities. Further elucidation of the usefulness of IFN-g release assays used in health-care workers pointed toward refinement in our understanding of the optimal use of IFN-g release assays in clinical settings. Several papers added to our knowledge of the immunology of TB, and this work seems especially important in light of a disappointing late phase 2b vaccine trial. Finally, several papers in the mouse model pointed toward important trials using existing TB drugs in novel ways to achieve durable cures in patients with drugsusceptible and drug-resistant active disease. This review focuses on work published in the Journal and highlights important advances in other publications.

Nontuberculous Mycobacterial Disease The Journal published two clinical studies in 2013 of patients in the United States with

nontuberculous mycobacterial (NTM) lung disease. Although the study populations evaluated include similar populations of predominately white female patients, the lines of investigation were distinctly different. Kartalija and colleagues at National Jewish Health compared 103 patients with NTM lung disease with 110 age-matched control subjects and found a distinct body morphotype (patients with NTM were taller, thinner and more likely to have skeletal abnormalities such as scoliosis and pectus excavatum), altered adipokine body fat relationships, and lower stimulated whole-blood IFN-g and IL-10 levels (1). These findings confirmed that there is a predisposing immunophenotype to NTM, and they suggest avenues for further investigation. Fowler and colleagues and the National Institutes of Health compared the abnormal nasal nitric oxide production, ciliary beat frequency, and tolllike receptor responses in epithelium of 58 patients with NTM lung disease compared with 40 healthy control subjects (2). They found that patients with NTM had low nasal nitric oxide production and low ciliary beat frequency as well as abnormal responses to agonists of several toll-like receptors important for normal immune responses. Both studies pose questions for further investigation into mechanisms for susceptibility to NTM lung disease and also raise question about how the very different findings of the studies may be related. Perhaps the challenges of identifying

effective treatment for NTM lung disease are to a greater extent attributable to host-related factors rather than specific antimicrobial drug regimens.

TB Basic Science

Four articles published in the Journal in 2013 drew attention to important aspects of TB pathogenesis and host immune responses. They paint a picture of a very complex puzzle, and certainly we should remember that despite all manner of immune dysregulation in individual patients, chemotherapy remains the most effective therapeutic modality. These papers add considerably to our understanding of disease pathology and especially provide important insights for vaccine development. Semple and colleagues studied the role of T regulatory cells (T-Regs) in inhibiting the growth and metabolism of Mycobacterium tuberculosis in alveolar and blood-derived macrophages recovered from patients with TB (3). In general, T-Regs are known to down-regulate effector functions of CD41 and CD81 T cells, and they have been shown to have a role in autoimmunity. In this experiment, investigators sampled blood and alveolar macrophages from patients with TB and healthy control subjects. They infected the macrophages with a virulent laboratory strain of M. tuberculosis, H37Rv, and

( Received in original form February 3, 2014; accepted in final form March 7, 2014 ) Correspondence and requests for reprints should be addressed to Neil W. Schluger, M.D., Columbia University Medical Center, 622 West 168th Street, New York, NY 10032. E-mail: [email protected] Am J Respir Crit Care Med Vol 189, Iss 8, pp 894–898, Apr 15, 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1164/rccm.201402-0210UP Internet address: www.atsjournals.org

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PULMONARY, SLEEP, AND CRITICAL CARE UPDATE cocultured the cells with autologous T-Regs and PPD-primed T-Reg–depleted effector cells. They found that T-Regs were present in higher numbers in blood and bronchoalveolar lavage samples from patients with TB as compared with those with latent TB infection. Furthermore, they demonstrated that restriction of mycobacterial growth within macrophages was significantly diminished in the presence of T-Regs cocultured with the PPD-primed effector cells. Notably, the lungs were enriched for CD41 T-Regs as compared with blood, and the authors concluded that CD41 CD251 FoxP31 T-Regs inhibit adaptive immune responses to mycobacteria in the lungs and thus are permissive for bacterial replication. This study is particularly notable for having been performed in humans, a difficult task indeed, but one that adds great strength to the findings and their implications for understanding host immune responses to TB. A related investigation described suppression of T-cell function in patients with active TB and recently acquired latent infection through the actions of myeloidderived suppressor cells. Nelita Du Plessis and colleagues took blood samples from South African patients with TB and their infected household contacts and analyzed the number of myeloid-derived suppressor cells at the sites of disease (4). As controls, they used samples from patients with lung cancer and from uninfected (tuberculin skin test [TST]negative) household contacts. In blood and pleural fluid samples from patients with TB, increased numbers of myeloid-derived suppressor cells were found, and these cells had considerable ability to inhibit T-cell function, as assessed in an allogeneic mixed lymphocyte reaction. In fact, myeloid-derived suppressor cells from both patients with TB and their TST-positive household control subjects impaired CD41 T-cell function, although this effect was more pronounced in cells taken from patients with TB than in those from their infected household contacts. Cytokines associated with these functions included IL-1, IL-6, IL-8, granulocyte colony–stimulating factor, and monocyte chemoattractant protein-1, whereas production of granulocyte– macrophage colony–stimulating factor and macrophage inflammatory protein-1 was reduced. The implications of this are that local immune dysregulation can be responsible for disease manifestations. (One cannot help noting that Verdi’s opera La Traviata, in which the heroine of

course tragically dies of TB, was based on the life of Marie Du Plessis!). The mechanism of tissue destruction in active TB was investigated by Radha Gopal and a large group of collaborators in a study that demonstrated an important role for S100 proteins in TB pathogenesis (5). These investigators showed that lung inflammation and destruction are mediated through accumulation of neutrophils that produce S100A8/A9 proteins locally. “Functional” granulomas that maintain the latent state of infection were not characterized by the elaboration of S100 proteins, but the inflammatory granulomas from patients with active disease were. Perhaps most intriguing in this study was the finding that S100 protein levels were elevated in the blood of patients with TB as compared with control subjects with latent infection, suggesting that this measurement could be useful in distinguishing active disease from latent infection. Furthermore, levels of serum S100 proteins seemed to correlate with lung pathology, indicating that this could be a useful marker of disease severity. Interestingly, S100 proteins seemed to have no role in controlling the bacterial population, suggesting that inhibition of S100 could limit lung pathology without impairing host antibacterial responses. However, it would be intriguing to consider whether S100 could be used as a biomarker of disease severity in clinical trials, as extensive cavitary disease is known to be a risk factor for relapse after treatment completion. A group of investigators from several experienced vaccine development groups (South Africa Tuberculosis Vaccine Initiative, GlaxoSmithKline, and Aeras Global TB Vaccine Foundation) conducted a phase 1 trial of a TB vaccine called M72/AS01 in South African adults and demonstrated that this vaccine induced high frequencies of T cells believed to be important in the adaptive immune response (6). In this experiment, the M72/AS01 vaccine, a recombinant fusion protein vaccine made with several potent immunostimulatory adjuvants, was tested in healthy South Africa adults for immunogenicity and safety. The fusion proteins in the vaccine are found in both M. tuberculosis and bacillus Calmette-Gu´erin (BCG) and are capable of inducing T-cell responses in healthy TST-positive but not -negative adults. In the present experiment, the vaccine was safe and induced robust and long-lasting Th1 cytokine responses. The

Pulmonary, Sleep, and Critical Care Update

T-cell responses induced by the vaccine were quite complex, and, importantly, they included stimulation of Th17 cells, which are believed to be important in protection from TB disease through their ability to recruit IFN-g–producing cells to the lungs, where they can inhibit mycobacterial growth. The positive results and encouraging immune response generated in the M72/AS01 trial just discussed are tempered by the disappointing results of the phase IIb MVA85 trial this year, published in June in The Lancet (7). In this highly anticipated, large phase 2 trial, healthy infants aged 4 to 6 months who had previously received BCG vaccine received a dose of MVA85A or a placebo, and the cohort was followed every 6 months for up to 3 years. A total of 2,797 infants were vaccinated. The number of systemic and/or serious adverse events between the experimental and placebo groups was not different. However, the incidence of TB in the follow-up period was nearly identical in the vaccinated and control groups: 2% of the experimentally vaccinated group developed TB in the follow-up period, and 3% of the control vaccinated infants did. The calculated vaccine efficacy was only 17.3%, far below the level of protection needed to prevent TB disease. Although the vaccine did induce MVA85A-specific T-cell responses, these responses were not as robust as had been seen in the preclinical animal studies or in some human trials. The results of this trial call into question the whole enterprise of selecting vaccine candidates based on current assumptions about immune correlates of protection against either initial infection with M. tuberculosis or from progression from latent infection to active disease. It has been well established that the type II interferons (particularly IFN-g are critical in host defense against TB. An important insight into the regulation of IFN-g responses was contributed by Teles and colleagues, who demonstrated that type I interferons (IFN-a and IFN-b), which are commonly produced during viral infections as an important host defense mechanism, can inhibit production of IFN-g, leading to loss of control against TB (and leprosy [8]). Epidemiology

Three articles published in the Journal in 2013 further our understanding of the epidemiologic features of TB transmission using unique and very different approaches. 895

PULMONARY, SLEEP, AND CRITICAL CARE UPDATE In the latest of a series of successively larger community-wide epidemiologic studies of TB conducted among residents of San Francisco, Suwanpimolkul and colleagues describe use of molecular epidemiologic techniques to describe the more rapid decline of the case rates due to secondary transmission from 1991 to 2009 among those born in the United States compared with foreign-born persons (9). Beginning in 2000, population-based analysis was feasible for the U.S.-born and the three largest foreign-born populations (from China, the Philippines, and Mexico) revealing unique clinical, microbiological, and epidemiologic differences that may inform specific TB control measures. The higher rates due to secondary transmission for cases among U.S.-born individuals in the San Francisco study were also observed in a large multicenter study of the transmission of multidrug-resistant (MDR) TB published by Moonan and colleagues in The Lancet Infectious Diseases in 2013 (10). Consent for interviews was obtained in 92 of 168 patients with MDR TB reported in eight centers during 2007 to 2009, of whom 86% were foreign born. Approximately one-fifth of cases were considered imported cases owing to diagnosis in foreign-born persons within 3 months of arrival in the United States (three with extensively drug-resistant TB) and another one-fifth due to transmission within the United States. The majority were attributed to reactivation of infection with MDR TB acquired years before U.S. entry. The frequency of transmission was 2.9-fold higher from cases among U.S.-born than foreign-born persons, but because of the greater number of cases among the latter, half of secondary cases resulted from transmission from foreign-born cases. The World Health Organization estimates that not even 20% of the 500,000 new MDR TB cases globally each year are diagnosed, much less effectively treated. Ongoing transmission of MDR TB can be expected in both developed and developing countries until safe and effective short-course regimens are developed and made available. In contrast to the San Francisco study, results of which were largely driven by the arrival of individuals infected with M. tuberculosis in their country of birth, the other two articles seek to address the important topic of ongoing transmission of TB in high-burden countries. Jones-L´opez and colleagues conducted contact 896

investigations for household members of 96 patients diagnosed in Kampala, Uganda with acid-fast bacillus (AFB)-positive sputum specimens (11). This was the first study to show the value of the cough aerosol sampling system (CASS) in stratifying the risk of transmission, defined as baseline to 6-week conversion to positive results by TST and/or IFN-g release assay (IGRA). The CASS category of “high aerosol” production, present in only 25 (26%) of the patients, was associated with a 5- to 10-fold higher rate of transmission, independent of AFB smear grading. Whether CASS can be implemented as a tool in TB control is yet to be determined, but these data help us understand why some AFB-positive patient are efficient transmitters and similar ones are not. Dowdy and colleagues modeled the relative effectiveness of strategies for reducing the transmission and thus the future incidence of TB in high-burden TB communities where most of the 1.4 million global TB deaths occur each year. Of the three strategies evaluated, two involve improvements applicable to individuals with symptoms of TB, specifically more accurate and rapid diagnostics and reducing delays in receiving evaluation and treatment. The modeling suggests that the third strategy of active case finding (including in part the process of contact investigations) for detection and treatment of subclinical cases of TB could be more effective than the first two, depending on an unknown—the relative infectiousness of subclinical cases (12). Related to this topic, the results of the large, randomized community and household intervention trial in southern Africa (ZAMSTAR) were also reported in 2013 and disappointingly showed no significant reduction in the incidence of TB or TB infection in schoolchildren in the study arms of enhanced community access to AFB microscopy or interventions to improve TB-HIV services for household members of individuals with new TB cases (13). Perhaps the data from this study will help inform further evaluation of intervention strategies for TB, whether in the form of future community intervention trials or modeling studies. Diagnostics

In 2010, the United States Centers for Disease Control and Prevention published

recommendations that IGRA could be used instead of the Mantoux TST for the diagnosis of latent TB infection, especially for those with prior vaccination with BCG or unlikely to return for the TST interpretation. Over a decade later, IGRA is increasingly being used, although the challenges in interpreting the results remain to be completely understood. Three articles and an editorial on the topic of IGRA published in the Journal in 2013 improve our understanding of some of the remaining puzzles, including the meaning of the high frequency (60% or more) of reversion of positive IGRA test results in repeat testing and the use of IGRA to measure the effectiveness of treatment for latent TB infection. The two studies of the QuantiFERON-TB Gold assay both involve largely low-risk populations in the United States, although both studies lack individual-level data on risk of prior TB exposure, vaccination with BCG, and TST results. The study reported by Slater and colleagues of more than 9,000 health-care workers undergoing annual repeat testing found a 4% rate of conversion to a positive test result that was interpreted as false positive based on comparison with the historical TST conversion rate of 0.4%, and a reversion from a positive to negative result in more than 60% at a 60-day followup (14). Even after accounting for reversions, however, there was still a higher apparent rate of infection as measured by IGRA compared with TST. These results are not easily explained and highlight the difficulty of developing new assays for latent infection in the absence of a true gold standard. The study by Metcalfe and colleagues examined one of the potential components of the variability in results by merely repeating the ELISA assay on the residual stimulated plasma for a subset of individuals whose assay responses were at least 0.25 IU/ml (15). Discordant results were observed in the repeat ELISA for 9% of repeats with initial negative results and 7% when the initial result was positive. As Mancuso and colleagues point out in the editorial, the predictive value of a positive test result will be diminished when applied in a low-risk population, a problem not resolved by the introduction of the IGRA (16). The article by Adetifa demonstrates the value of a well-designed randomized clinical trial in answering an important question:

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PULMONARY, SLEEP, AND CRITICAL CARE UPDATE Can the IGRA responses be used as a biomarker for response to treatment of latent TB infection (17)? The answer is clearly no: about 20% of contacts with a positive TST and a positive IFN-g enzyme-linked immunospot assay had reversion to a negative IGRA response at 1 month in both the placebo and 6-month isoniazid arms without decline at a 1-year follow-up. Screening for study eligibility did show the apparent improved specificity of the IGRA in this population in Gambia. Positive TSTs were detected in 39% of 1,659 household contacts, but only 33% of the TST-positive contacts had a positive IGRA, presumably reflecting the effect of prior BCG vaccination on the TST. Clinical Trials

Two studies published in the Journal in 2014 examined the role of quinolone antibiotics in the treatment of TB. In a trial of levofloxacin as compared with moxifloxacin in patients with MDR TB in South Korea, levofloxacin seemed to perform just as well as moxifloxacin, although moxifloxacin is known to have a more favorable minimal inhibitory concentration against M. tuberculosis in vivo as compared with levofloxacin (18). An editorial that accompanied that study pointed out several potential shortcomings in the conduct of the trial but concluded that overall, based on present published data, there seems to be rough equivalence between the two drugs in actual clinical use (19). A murine study further examined the role of moxifloxacin and levofloxacin in second-line regimens for TB. In this study, moxifloxacin-containing regimens and levofloxacin-containing regimens performed similarly in initial phases of treatment, but the moxifloxacin-based regimens were associated with better bacterial killing 4 and 5 months after initiation of therapy (20). Interestingly, this advantage for moxifloxacin was largely eliminated if pyrazinamide was included in the regimen. This may in part explain the results of the South Korean trial in humans, as 82% of the patients in the levofloxacin arm and 69% of patients in the moxifloxacin arm were also receiving pyrazinamide. Other murine studies of antituberculosis drugs focused on optimal

use of existing medications. Over the past several years, there has been a growing appreciation that the most potent class of antituberculosis drugs, the rifamycins, have not been used to maximum advantage, primarily because they have been used at the lower end of their effective dosing range (21). A number of ongoing clinical trials in humans are examining higher doses of several members of this class, including rifampin and rifapentine. Using the mouse model of TB, a Dutch group led by Jurrian de Steenwinkel showed that the maximum tolerated dose of rifampin was an astounding 160 mg/kg/d (in humans, treatment doses are generally 10 mg/kg/d) (22). At that very high dose, important pharmacokinetic parameters such as Cmax and AUC0-24 were substantially higher than those achieved with conventional dosing. Rifampin given to the mice at a dose of 80 mg/kg/d in combination with isoniazid resulted in complete sterilization without relapse after only 9 weeks of treatment. These results will surely bolster those examining the role of higher doses of rifamycins in humans. The potential role of clofazimine, another old and by now infrequently used antituberculosis drug, was assessed in a murine trial conducted by Jacques Grosset and colleagues (23). This drug has generally been regarded as less potent than many of the other second-line agents, and problems with skin hyperpigmentation have further limited its use. However, because of the emergence of MDR TB and the shallow pipeline of new agents in clinical development, interest has been rekindled. In this study, Grosset and colleagues (23) treated mice infected with TB with a second-line regimen of moxifloxacin, ethambutol, pyrazinamide, and (for the initial 2 months) amikacin with or without clofazimine. All mice that received clofazimine were culture negative after 5 months (with an ultimate relapse rate of 7%), whereas mice that did not received clofazimine remained culture positive through 9 months of treatment. A fascinating study from William Bishai and his group working in Baltimore and Durban examined the potential role of verapamil as adjunctive therapy for TB (24). A prior study from another group had demonstrated a novel mechanism of drug tolerance in mycobacteria that involved an efflux pump that could be inhibited in vitro

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by addition of verapamil (25). Efflux pumps lower intracellular drug concentrations and make error-prone replication more likely, increasing the chance of a minimal inhibitory concentration–changing mutation. In the study by Gupta and colleagues (24), researchers tested the effect of adjunctive verapamil in a murine model, using C3HeB/FeJ mice, which are capable of forming necrotizing granulomas. Addition of verapamil accelerated bacterial clearance, allowed for treatment shortening, and lowered relapse rates. Although widespread use of verapamil (especially in the higher doses needed to overcome the induction of metabolism caused by rifampin) may be unrealistic in TB, the use of efflux inhibitors in general will be an intriguing avenue to pursue in clinical trials in the future. In a different vein, an important implementation science study was published that examined the role of the GenXpert MTB/RIF technology in affecting better outcomes for patients (26). This randomized trial conducted in South Africa demonstrated positive effects of the technology as manifested by more patients starting same-day treatment, more culturepositive patients starting therapy, and a shorter time to treatment. However, there was no overall effect on TB mortality. This study points out the challenges of integrating this important new technology into TB control programs in a manner that affects overall morbidity and mortality. TB Research Funding

In some ways, the most important publication related to TB research this past year was the “2013 Report on Tuberculosis Research Funding Trends, 2005–2012” published by Treatment Action Group (27). This report demonstrated the dramatic underfunding of TB research globally (for basic science, diagnostics, drugs, and vaccines) compared with other similar public health crises, such as HIV. Furthermore, and most worrying, TB research funding globally actually declined in 2013. If this trend continues, the chance for significant progress in controlling one of the world’s great public health challenges will remain unlikely. n Author disclosures are available with the text of this article at www.atsjournals.org.

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PULMONARY, SLEEP, AND CRITICAL CARE UPDATE References 1. Kartalija M, Ovrutsky AR, Bryan CL, Pott GB, Fantuzzi G, Thomas J, Strand MJ, Bai X, Ramamoorthy P, Rothman MS, et al. Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am J Respir Crit Care Med 2013;187:197–205. 2. Fowler CJ, Olivier KN, Leung JM, Smith CC, Huth AG, Root H, Kuhns DB, Logun C, Zelazny A, Frein CA, et al. Abnormal nasal nitric oxide production, ciliary beat frequency, and Toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium. Am J Respir Crit Care Med 2013;187:1374–1381. 3. Semple PL, Binder AB, Davids M, Maredza A, van Zyl-Smit RN, Dheda K. Regulatory T cells attenuate mycobacterial stasis in alveolar and blood-derived macrophages from patients with tuberculosis. Am J Respir Crit Care Med 2013;187:1249–1258. 4. du Plessis N, Loebenberg L, Kriel M, von Groote-Bidlingmaier F, Ribechini E, Loxton AG, van Helden PD, Lutz MB, Walzl G. Increased frequency of myeloid-derived suppressor cells during active tuberculosis and after recent mycobacterium tuberculosis infection suppresses T-cell function. Am J Respir Crit Care Med 2013;188: 724–732. 5. Gopal R, Monin L, Torres D, Slight S, Mehra S, McKenna KC, Fallert Junecko BA, Reinhart TA, Kolls J, Baez-Saldaña ´ R, et al. S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am J Respir Crit Care Med 2013;188:1137–1146. 6. Day CL, Tameris M, Mansoor N, van Rooyen M, de Kock M, Geldenhuys H, Erasmus M, Makhethe L, Hughes EJ, Gelderbloem S, et al. Induction and regulation of T-cell immunity by the novel tuberculosis vaccine M72/AS01 in South African adults. Am J Respir Crit Care Med 2013;188:492–502. 7. Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, Shea JE, McClain JB, Hussey GD, Hanekom WA, et al.; MVA85A 020 Trial Study Team. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013;381: 1021–1028. 8. Teles RM, Graeber TG, Krutzik SR, Montoya D, Schenk M, Lee DJ, Komisopoulou E, Kelly-Scumpia K, Chun R, Iyer SS, et al. Type I interferon suppresses type II interferon-triggered human antimycobacterial responses. Science 2013;339:1448–1453. 9. Suwanpimolkul G, Jarlsberg LG, Grinsdale JA, Osmond D, Kawamura LM, Hopewell PC, Kato-Maeda M. Molecular epidemiology of tuberculosis in foreign-born persons living in San Francisco. Am J Respir Crit Care Med 2013;187:998–1006. 10. Moonan PK, Teeter LD, Salcedo K, Ghosh S, Ahuja SD, Flood J, Graviss EA. Transmission of multidrug-resistant tuberculosis in the USA: a cross-sectional study. Lancet Infect Dis 2013;13:777–784. 11. Jones-Lopez ´ EC, Namugga O, Mumbowa F, Ssebidandi M, Mbabazi O, Moine S, Mboowa G, Fox MP, Reilly N, Ayakaka I, et al. Cough aerosols of Mycobacterium tuberculosis predict new infection: a household contact study. Am J Respir Crit Care Med 2013;187: 1007–1015. 12. Dowdy DW, Basu S, Andrews JR. Is passive diagnosis enough? The impact of subclinical disease on diagnostic strategies for tuberculosis. Am J Respir Crit Care Med 2013;187:543–551.

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13. Ayles H, Muyoyeta M, Du Toit E, Schaap A, Floyd S, Simwinga M, Shanaube K, Chishinga N, Bond V, Dunbar R, et al.; ZAMSTAR team. Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR communityrandomised trial. Lancet 2013;382:1183–1194. 14. Slater ML, Welland G, Pai M, Parsonnet J, Banaei N. Challenges with QuantiFERON-TB Gold assay for large-scale, routine screening of U.S. healthcare workers. Am J Respir Crit Care Med 2013;188: 1005–1010. 15. Metcalfe JZ, Cattamanchi A, McCulloch CE, Lew JD, Ha NP, Graviss EA. Test variability of the QuantiFERON-TB gold in-tube assay in clinical practice. Am J Respir Crit Care Med 2013;187:206–211. 16. Mancuso JD, Bernardo J, Mazurek GH. The elusive “gold” standard for detecting Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 2013;187:122–124. 17. Adetifa IM, Ota MO, Jeffries DJ, Lugos MD, Hammond AS, Battersby NJ, Owiafe PK, Donkor SD, Antonio M, Ibanga HB, et al. Interferon-g ELISPOT as a biomarker of treatment efficacy in latent tuberculosis infection: a clinical trial. Am J Respir Crit Care Med 2013;187:439–445. 18. Koh WJ, Lee SH, Kang YA, Lee CH, Choi JC, Lee JH, Jang SH, Yoo KH, Jung KH, Kim KU, et al. Comparison of levofloxacin versus moxifloxacin for multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2013;188:858–864. 19. Schluger NW. Fluoroquinolones in the treatment of tuberculosis: which is best? Am J Respir Crit Care Med 2013;188:768–769. 20. Ahmad Z, Tyagi S, Minkowski A, Peloquin CA, Grosset JH, Nuermberger EL. Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis. Am J Respir Crit Care Med 2013;188:97–102. 21. Peloquin C. What is the ‘right’ dose of rifampin? Int J Tuberc Lung Dis 2003;7:3–5. 22. de Steenwinkel JE, Aarnoutse RE, de Knegt GJ, ten Kate MT, Teulen M, Verbrugh HA, Boeree MJ, van Soolingen D, Bakker-Woudenberg IA. Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model. Am J Respir Crit Care Med 2013;187:1127–1134. 23. Grosset JH, Tyagi S, Almeida DV, Converse PJ, Li SY, Ammerman NC, Bishai WR, Enarson D, Trebucq ´ A. Assessment of clofazimine activity in a second-line regimen for tuberculosis in mice. Am J Respir Crit Care Med 2013;188:608–612. 24. Gupta S, Tyagi S, Almeida DV, Maiga MC, Ammerman NC, Bishai WR. Acceleration of tuberculosis treatment by adjunctive therapy with verapamil as an efflux inhibitor. Am J Respir Crit Care Med 2013;188: 600–607. 25. Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, Humbert O, Edelstein PH, Cosma CL, Ramakrishnan L. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 2011;145:39–53. 26. Theron G, Zijenah L, Chanda D, Clowes P, Rachow A, Lesosky M, Bara W, Mungofa S, Pai M, Hoelscher M, et al.; TB-NEAT team. Feasibility, accuracy, and clinical effect of point-of-care Xpert Mtb/Rif testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. Lancet 2014;383: 424–435. 27. Frick M, Jimenez-Levi ´ E. 2013 Report on tuberculosis research funding trends, 2005–2012. New York, NY: Treatment Action Group; 2013.

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