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 renement 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 ndings conrmed 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
ndings 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 specic
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: ns311@cumc.columbia.edu
Am J Respir Crit Care Med Vol 189, Iss 8, pp 894898, Apr 15, 2014
Copyright 2014 by the American Thoracic Society
DOI: 10.1164/rccm.201402-0210UP
Internet address: www.atsjournals.org

894

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 8 | April 15 2014

PULMONARY, SLEEP, AND CRITICAL CARE UPDATE

cocultured the cells with autologous T-Regs
and PPD-primed T-Regdepleted 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 signicantly 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 difcult task indeed, but one that adds great
strength to the ndings 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 uid 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 colonystimulating factor,
and monocyte chemoattractant protein-1,
whereas production of granulocyte
macrophage colonystimulating factor and
macrophage inammatory protein-1 was
reduced. The implications of this are that
local immune dysregulation can be
responsible for disease manifestations.
(One cannot help noting that Verdis
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
inammation 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 inammatory granulomas
from patients with active disease were.
Perhaps most intriguing in this study was
the nding 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-Guerin
(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-gproducing 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 efcacy was only 17.3%, far below
the level of protection needed to prevent TB
disease. Although the vaccine did induce
MVA85A-specic 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.
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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 specic 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-fth 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-fth 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-Lopez
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 rst
study to show the value of the cough
aerosol sampling system (CASS) in
stratifying the risk of transmission, dened
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 efcient
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,
specically more accurate and rapid
diagnostics and reducing delays in
receiving evaluation and treatment. The
modeling suggests that the third strategy
of active case nding (including in part
the process of contact investigations) for
detection and treatment of subclinical
cases of TB could be more effective
than the rst two, depending on an
unknownthe 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
signicant 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
difculty 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:

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 8 | April 15 2014

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
specicity 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 reecting 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 levooxacin as compared with
moxioxacin in patients with MDR TB in
South Korea, levooxacin seemed to
perform just as well as moxioxacin,
although moxioxacin is known to have
a more favorable minimal inhibitory
concentration against M. tuberculosis
in vivo as compared with levooxacin (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 moxioxacin and levooxacin in
second-line regimens for TB. In this study,
moxioxacin-containing regimens and
levooxacin-containing regimens
performed similarly in initial phases of
treatment, but the moxioxacin-based
regimens were associated with better
bacterial killing 4 and 5 months after
initiation of therapy (20). Interestingly, this
advantage for moxioxacin 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 levooxacin
arm and 69% of patients in the
moxioxacin 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
moxioxacin, 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
efux pump that could be inhibited in vitro

Pulmonary, Sleep, and Critical Care Update

by addition of verapamil (25). Efux pumps

lower intracellular drug concentrations
and make error-prone replication more
likely, increasing the chance of a minimal
inhibitory concentrationchanging
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 efux 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, 20052012
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 signicant progress in controlling one
of the worlds 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;187:197205.
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;187:13741381.
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;187:12491258.
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:
724732.
5. Gopal R, Monin L, Torres D, Slight S, Mehra S, McKenna KC, Fallert
Junecko BA, Reinhart TA, Kolls J, Baez-Saldaa

R, et al. S100A8/A9
proteins mediate neutrophilic inammation and lung pathology during
tuberculosis. Am J Respir Crit Care Med 2013;188:11371146.
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;188:492502.
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 efcacy of MVA85A, a new
tuberculosis vaccine, in infants previously vaccinated with BCG:
a randomised, placebo-controlled phase 2b trial. Lancet 2013;381:
10211028.
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;339:14481453.
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;187:9981006.
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;13:777784.
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:
10071015.
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;187:543551.

898

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;382:11831194.
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:
10051010.
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;187:206211.
16. Mancuso JD, Bernardo J, Mazurek GH. The elusive gold standard for
detecting Mycobacterium tuberculosis infection. Am J Respir Crit
Care Med 2013;187:122124.
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 efcacy in latent tuberculosis
infection: a clinical trial. Am J Respir Crit Care Med 2013;187:439445.
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 levooxacin versus
moxioxacin for multidrug-resistant tuberculosis. Am J Respir Crit
Care Med 2013;188:858864.
19. Schluger NW. Fluoroquinolones in the treatment of tuberculosis: which
is best? Am J Respir Crit Care Med 2013;188:768769.
20. Ahmad Z, Tyagi S, Minkowski A, Peloquin CA, Grosset JH,
Nuermberger EL. Contribution of moxioxacin or levooxacin in
second-line regimens with or without continuation of pyrazinamide in
murine tuberculosis. Am J Respir Crit Care Med 2013;188:97102.
21. Peloquin C. What is the right dose of rifampin? Int J Tuberc Lung Dis
2003;7:35.
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
efcacy in tuberculosis treatment using a murine model. Am J Respir
Crit Care Med 2013;187:11271134.
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;188:608612.
24. Gupta S, Tyagi S, Almeida DV, Maiga MC, Ammerman NC, Bishai WR.
Acceleration of tuberculosis treatment by adjunctive therapy with
verapamil as an efux inhibitor. Am J Respir Crit Care Med 2013;188:
600607.
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 efux
mechanism. Cell 2011;145:3953.
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:
424435.
27. Frick M, Jimenez-Levi

E. 2013 Report on tuberculosis research funding

trends, 20052012. New York, NY: Treatment Action Group; 2013.

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 8 | April 15 2014