Pulmonary, Sleep, and Critical Care Updates

Update in Tuberculosis and Nontuberculous

Mycobacterial Disease 2010
Wing Wai Yew
1
, Giovanni Sotgiu
2
, and Giovanni Battista Migliori
3
1
Hong Kong Tuberculosis, Chest, and Heart Diseases Association, Hong Kong, China;
2
Department of Biomedical Sciences, University of Sassari,
Sassari, Italy; and
3
World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S. Maugeri, Care and Research
Institute, Tradate, Italy
Tuberculosis (TB) still remains an important infectious disease
and health problem worldwide in 2010. The estimates of its
global burden from the World Health Organization (WHO, Ge-
neva, Switzerland) in 2009 were 9.4 million incident cases, 14 mil-
lion prevalent cases, and 1.68 million deaths (with 0.38 million in
HIV-positive individuals) (1). Drug resistance and HIV coinfec-
tion continue to pose a challenge to the global control of TB.
These scenarios have underscored the tremendous enthusiasm
sustaining TB research globally and in the United States (2). In
addition, the prevalence of infection/disease due to nontuber-
culous mycobacteria (NTM) is escalating in various parts of the
globe (3). In 2010, 24 studies on TB and NTM were published in
the Journal. These articles are reviewed, alongside others pub-
lished elsewhere, in this current update.
PATHOGENESIS, IMMUNOLOGY, AND GENETICS
OF TUBERCULOSIS
Resuscitation-promoting factors (Rpfs), a family of proteins pro-
duced by Mycobacterium tuberculosis, acting on the bacterial
cell wall, can stimulate regrowth of inert and otherwise noncul-
turable bacteria, and enable reactivation of chronic TB in mice.
Mukamolova and colleagues determined whether Rpf-dependent
tubercle bacilli were present in human sputum, and explored the
effect of anti-TB chemotherapy (4). Most samples were domi-
nated by a population of M. tuberculosis cells that could be cul-
tured only by addition of Rpf. During chemotherapy this occult
population increased relative to the bacilli that could be recov-
ered by conventional culture, suggesting phenotypic tolerance of
the former cells to rifampin. These intriguing bacterial growth
factors would likely be relevant in the pathogenesis of TB, espe-
cially in relation to the mycobacterial persisters.
The cell-mediated immune responses of the host in TB,
involving macrophages and various types of lymphocytes,
are regarded as complex and not fully unraveled (5). The pro-
tective response is much studied in relation to potential vac-
cine development.
Chen and colleagues investigated the mechanisms underlying
the progression of TB infection to active disease, in particular
regarding the regulatory role of helper T (Th) type 17 cells (6).
The association between Th17 response and the clinical outcome
of M. tuberculosis infection suggests that Th17 cells are more
likely to play an important role in prevention of disease devel-
opment and progression, than in resistance to primary infection.
Jeyanathan and colleagues examined the immune properties
and mechanisms of maintenance of airway luminal M. tuberculosis
antigenspecic CD8
1
T cells, using a model of adenovirus-
based intranasal immunization (7). Such immunization was
found to elicit persistence of antigen-specic CD8
1
T cells in
the airway lumen, which displayed an activated effector mem-
ory phenotype, different from those cells located in the periph-
eral tissues. Airway luminal T cells continued to proliferate in
an antigen-dependent manner, and could be maintained even
in the absence of peripheral T-cell recruitment. Thus, the lungs
would be protected against M. tuberculosis challenge through
the airway. These ndings may have potential value in the de-
sign of new TB vaccines, especially regarding the use of a non-
parenteral route of administration.
This study by Tena-Coki and colleagues (8) compared CD4
1
and CD8
1
T-cell cytokine expression and effector memory phe-
notype in bacillus Calmette-Gue rin (BCG)vaccinated children
after in vitro stimulation with mycobacterial antigens, Ag85B
and TB 10.4, contained in novel TB vaccines presently under-
going clinical trials. It was found that higher frequencies of
CD4
1
T cells, expressing IFN-g, IL-2, or both, were present
in children with TB, but there was no difference in phenotype
between children with and without HIV infection. The substan-
tial frequencies of mycobacteria-specic effector CD4
1
and
CD8
1
T-cell responses detected allude to the rationale of on-
going trials of these new vaccines in children, including those
with HIV positivity.
The mycobacterial antigen heparin-binding hemagglutinin
(HBHA) is known to induce strong IFN-g responses by
circulating lymphocytes from subjects with latent tuberculosis
infection (LTBI) (9). Place and colleagues studied the HBHA-
specic IFN-g responses at the site of TB disease (10). They
found that the percentages of HBHA-induced IFN-g
1
alveolar
and pleural lymphocytes, as assessed by ow cytometry and
enzyme-linked immunosorbent assay, were higher for pulmo-
nary (P , 0.0001) and for pleural (P , 0.01) TB than for
non-TB control subjects. Local CD4
1
and CD8
1
T cells pro-
duced the HBHA-specic IFN-g, which was not suppressed by
T-regulatory lymphocytes, in contrast to the previous data on
circulating lymphocytes. These results may suggest a possible
role for HBHA in designing new TB vaccines and tools for the
rapid diagnosis of TB.
As the immunogenicity of new TB vaccines is commonly
assessed by measuring the frequency and cytokine expression
prole of T cells, Kagina and colleagues investigated whether
such parameters would correlate with protection against child-
hood TB after newborn vaccination with BCG (11). Infants
were followed up for 2 years to identify those who developed
(Received in original form February 22, 2011; accepted in nal form May 2, 2011)
Correspondence and requests for reprints should be addressed to Giovanni Battista
Migliori, M.D.,WHO Collaborating Centre for TB and Lung Diseases, Fonda-
zione S. Maugeri, Care and Research Institute, Tradate, 21049 Italy. E-mail:
giovannibattista.migliori@fsm.it
Am J Respir Crit Care Med Vol 184. pp 180185, 2011
DOI: 10.1164/rccm.201102-0325UP
Internet address: www.atsjournals.org
culture-positive TB. Infants who did not develop TB despite
exposure to index cases in their households, and another group
of randomly selected infants (never evaluated for TB), were
also enrolled for comparison. CD4
1
, CD8
1
, and gd
1
T cell
specic expression of IFN-g, tumor necrosis factor (TNF)-a,
IL-2, and IL-17 of these groups were measured, and no differ-
ences were found. The investigators concluded that the fre-
quency and cytokine prole of mycobacteria-specic T cells
did not correlate with protection against TB. Smith and col-
leagues performed a study to delineate which cytokines and
lymphocyte populations characterize the peripheral blood cell
mediated immune response after BCG vaccination, using multi-
plex bead array and intracellular cytokine staining (12). They
found a broad array of cytokine responses, notably IFN-g, from
CD4
1
and CD8
1
T cells as well as natural killer cells. However,
polyfunctional T cells (with several key cytokines coexpressed),
generally regarded as having a role in protective immunity, were
not detected in vaccinated adolescents who, based on earlier
epidemiological studies, should have developed protection
against pulmonary TB. It appears that further work needs to
be done to unravel the optimal way of assessing the protective
efcacy of a TB vaccine, due to imperfect understanding cur-
rently of the human immune response to M. tuberculosis.
Vulnerability to develop TB is determined by the virulence
of M. tuberculosis and by the genetic background of the host.
The TNF-a cytokine is essential to contain mycobacterial in-
fection. Moller and colleagues investigated four functionally
relevant polymorphisms in the TNF receptor 2encoding gene,
TNF receptor superfamily member 1B, for association with TB
susceptibility (13). Genotyping was performed in independent
populations from South Africa and Ghana, and the association
of the variants with TB was tested using two casecontrol asso-
ciation studies. Single-point and haplotype analysis in South
Africans revealed an association in the 39 untranslated region
of the investigated gene. The T allele of rs3397 alone and/or the
39 untranslated region haplotype GTT might confer protection
against TB, as both allele and haplotype frequencies were sig-
nicantly lower in case subjects than in control subjects. The
GTT genotype had previously been shown to increase the decay
of TNF receptor 2 messenger RNA, and messenger RNA de-
stabilization might represent a key molecular mechanism for TB
susceptibility. The ndings of this study reiterate the impor-
tance of TNF/TNF receptormediated immune responses in
the pathogenesis of TB (13, 14).
EPIDEMIOLOGY OF TUBERCULOSIS AND
LATENT TUBERCULOSIS INFECTION
In the United States and Europe, more than 50% of foreign-born
people have active TB, whereas in natives TB disease is affecting
mainly the older age groups (1, 2). Whereas in the 1950s in
the United States the rate of TB reactivation from LTBI was
0.100.16 cases per 100 person-years, a study by Horsburgh and
colleagues demonstrated that in the 1990s to 2000s it was 0.040
0.058 in HIV-negative individuals (15). The study also con-
rmed that (1) HIV infection was the strongest risk factor for
reactivation; (2) in immunocompetent individuals older than
50 years reactivation increased; and (3) reactivation rates in the
United States have declined substantially over the past decades.
Furthermore, ODonnell and colleagues (16) demonstrated
that both reactivation and recent TB transmission were in-
creased among black people in the United States, reiterating
that targeted LTBI screening and intensive contact tracing,
both followed by preventive treatment, are mandatory inter-
ventions to reduce the occurrence of TB in this at-risk popu-
lation (1619).
Evidence indicates how important it is, from an elimination
perspective, to implement this strategy in immigrant populations
to low TB incidence countries (2023).
Middelkoop and colleagues assessed the community-level im-
pact of highly active antiretroviral treatment (HAART) on TB
prevalence in South Africa through a follow-up cross-sectional
survey (24). TB prevalence in participants not infected with
HIV was found to be unchanged (P 0.90), whereas in partic-
ipants infected with HIV, the prevalence of treated and un-
treated TB declined from 4.0 to 2.3% (P 0.06) and from 5.2
to 1.3% (P 0.02), respectively. The proportion of untreated TB
in patients receiving HAART decreased markedly from 22 to
0% (P , 0.001). These ndings strongly underscore the current
recommendations to initiate early HAART in patients with TB
(25). Furthermore, Gandhi and colleagues conducted a retrospec-
tive observational study among patients with multidrug-resistant
TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) in
a setting with high HIV coinfection rates (26). They found that
the 1-year mortality for MDR-TB was 71%, and that of XDR-
TB was 83%; 40% of patients with MDR-TB and 51% of
patients with XDR-TB died within 30 days of sputum collection.
Although these formidable rates improved from 2005 to 2007, the
majority of deaths still occurred within the rst 30 days, and the
mortality rates were worse with a greater degree of drug resis-
tance. Thus, it is imperative to have early diagnosis and initiation
of HAART in HIV-infected patients with drug-resistant TB.
Availability of antiretroviral drugs and integration of TB and
HIV activities are key prerequisites to achieve a high treatment
success rate in patients coinfected with HIV and TB in the
United States (27) as well as in South Africa (28, 29).
Shin and colleagues demonstrated that 6% of patients with
MDR-TB developed XDR-TB during their treatment (30). The
presence of bilateral and cavitary lesions, prior exposure to a sec-
ond-line injectable drug, and each additional month in which
a patient failed to take at least 80% of the prescribed medications
were independently associated with increased hazard. These
results recapitulate the importance of programmatic delivery of
MDR-TB treatment, including directly observed therapy (25).
Kim and colleagues produced a timely reappraisal of the appro-
priateness of the current or revised denition of XDR-TB, versus
the earlier or original denition of this disease (31). The investi-
gators evaluated the treatment outcome and long-term survival
of patients with MDR-TB by stratication of cases according to
drug resistance patterns. Among all patients with MDR-TB, 5.3%
had XDR-TB by the revised denition. Such patients had the
lowest treatment success rate (29.3%) and the poorest long-
term survival, in comparison with XDR-TB as originally dened
and preXDR-TB with resistance to ooxacin or second-line in-
jectable drug(s). The ndings highlight the prognostic signicance
of the current denition of XDR-TB, that is, MDR-TB with ad-
ditional bacillary resistance to uoroquinolones and second-line
injectable agents (32), and the need to shed further light on the
clinical and public health features of XDR-TB (33, 34).
Tuberculosis among health care workers has become an in-
creasingly serious problem worldwide (35). In HIV-endemic
areas, MDR-TB and XDR-TB constitute especially formida-
ble issues (36).
Further published reviews on the association of tobacco
smoking and other forms of air pollution with TBand lung health
should also be notably emphasized (37, 38).
DIAGNOSIS OF TUBERCULOSIS AND LATENT
TUBERCULOSIS INFECTION
There has been some mounting enthusiasm in the use of IFN-
gbased assays (IGRAs) for the diagnosis of extrapulmonary
Pulmonary, Sleep, and Critical Care Updates 181
TB (39, 40). Patel and colleagues evaluated the diagnostic utility
of the RD1 antigenspecic enzyme-linked immunospot (ELI-
SPOT) assay in the diagnosis of tuberculous meningitis (TBM)
(41). A total of 140 patients (81% HIV-infected with a median
CD4
1
count of 160 cells/mm
3
) were studied. When comparing
the denite-TBM and non-TBM groups, the ELISPOT assay
(with a cutoff point of at least 228 spot-forming cells per 1
million mononuclear cells) was useful as a rule-in test: sensitiv-
ity was 58% and specicity was 94% . However, IGRA perfor-
mance improved when other rapid tests were concurrently used
to exclude bacterial and cryptococcal meningitis within the non-
TBM group. Thus, using this approach, the ELISPOT assay
(with a cutoff of at least 46 spot-forming cerebrospinal uid-
cells) became an excellent rule-in test: sensitivity, 82%; speci-
city, 100%; positive predictive value, 100%; and negative
predictive value, 68%. Furthermore, the ELISPOT assay was
found to have incremental diagnostic value compared with the
clinical prediction rule.
As the contribution of IGRAs to appropriate risk stratica-
tion of suspected TB cases has not been studied, Metcalfe and
colleagues embarked on a study to determine whether the addi-
tion of IGRA results to a clinical prediction model could im-
prove such risk delineation (42). Among 660 patients meeting
eligibility criteria, 10% had culture-proven TB. The odds of
active TB increased by 7% for each doubling of the IFN-g level.
The addition of quantitative IGRA results to objective clinical
data signicantly improved the clinical model performance, and
led to correct reclassication of 32% of TB suspects (P , 0.001)
into higher or lower risk categories. However, these quantita-
tive results did not improve appropriate risk reclassication be-
yond that provided by clinical assessment of risk: 4% (P 0.14).
As this latter information pertained to a highly experienced
center, further evaluation in other clinical settings was thought
to be warranted.
Leung and colleagues performed a prospective evaluation of
the development of TB among silicotic subjects with LTBI by
comparing the performance of the tuberculin skin test (TST)
and T-SPOT.TB (43). TB developed in 5.5% of 308 recruited
subjects (4.5% culture or histology conrmed) at an annual rate
of 2,247 (1,851) per 100,000 person-years. TB occurred in 7.4 and
1.9% of T-SPOT.TB-positive and -negative subjects, respectively,
whereas the corresponding values for the TST (cutoff, 10 mm)
were 6.4 and 3.9%, respectively. A positive T-SPOT.TB test sig-
nicantly predicted the subsequent development of TB with a rel-
ative risk of 4.5 (7.8 for culture- or histology-conrmed disease).
Consistent results were obtained after exclusion of subjects trea-
ted for LTBI and adjustment of potential confounders. Thus,
T-SPOT.TB was found to outperform the TST in the prediction
of development of TB in M. tuberculosisinfected subjects with
silicosis.
Amolecular-based test, with potential application at the point
of care, for rapid (,2 h) detection of M. tuberculosis and assess-
ment of its susceptibility to rifampin, has received much attention
(44), due to its capacity to promptly direct a patient to specialized
MDR-TB management after diagnosis (45).
TREATMENT OF TUBERCULOSIS AND LATENT
TUBERCULOSIS INFECTION
Swaminathan and colleagues evaluated the efcacy of a 6- versus
9-month intermittent treatment regimen (Reg6M vs. Reg9M) in
antiretroviral therapynaive HIV-infected patients with TB, us-
ing a randomized clinical trial (46). The 2-month intensive
phase comprised administration of ethambutol, isoniazid, rifam-
pin, and pyrazinamide, whereas in the 4- or 7-month continua-
tion phase, only isoniazid and rifampin were used. All drugs
were given three times weekly. Of 327 patients, 70% had
culture-positive pulmonary TB. The median CD4
1
T-cell count
was 160 cells/mm
3
and the median viral load was 155,000 copies/ml.
Favorable response to treatment of TB was similar by intent-to-
treat analysis (Reg6M, 83% and Reg9M, 76%; P not signicant).
Bacteriological recurrence was detected more often in Reg6M
than in Reg9M (15 vs. 7%; P , 0.05), although the overall recur-
rences were not signicantly different. By 36 months, 36% of
patients allocated to Reg6M and 35% of those to Reg9M had
died, with no statistically signicant difference between the regi-
mens. All 19 patients who failed treatment acquired rifamycin-
resistant TB, with initial bacillary resistance to isoniazid as
the main risk factor (4651). These data further underline the
messages from the WHO TB treatment guidelines and expert
reviews (25, 4951).
The current treatment for MDR-TB, as recommended by
guidelines, involves lengthy regimens that are associated with
poor tolerance (48, 51, 52).
Preliminary evidence demonstrating linezolid-associated ad-
verse events prevented its widespread use in second-line regi-
mens, except for the most severe cases (5356), and the need
for new approaches therefore appears to be even more urgent.
Van Deun and colleagues performed an observational study
to evaluate the effectiveness of standardized regimens for
patients with proven MDR-TB not previously treated with
second-line drugs (57). Using one of six standardized regimens,
with regimens adapted according to results of previous cohorts,
the most effective regimen was found to require a minimum of 9
months of gatioxacin, clofazimine, ethambutol, and pyrazina-
mide throughout the entire treatment period, supplemented by
prothionamide, kanamycin, and high-dose isoniazid during an
intensive phase of a minimum of 4 months. A relapse-free cure
was achieved in 87.9% of 206 patients. Major adverse drug
reactions were infrequent and manageable. Compared with 221
patients treated with regimens based on ooxacin and commonly
prothionamide throughout, the hazard of any adverse outcome
was much lower. These ndings allude to the possibility of using
newer uoroquinolones, especially at higher doses, in shortening
the duration of treatment of MDR-TB in chemotherapy-naive
patients. Further evaluation is, however, required in high HIV-
prevalence settings and in those with higher prevalence of initial
bacillary resistance to second-line drugs (58).
The rational use of uoroquinolones (the only new class of
anti-TB drugs introduced after rifampin) is of paramount impor-
tance, until new drugs appear in future (48, 51, 59).
The WHO, in the process of revising treatment guidelines for
MDR-TB (60), has launched a number of studies, with some
published (61). Clinical trials are clearly of paramount impor-
tance in enabling improvement of treatment of TB including
MDR-TB, but methodological issues still provide substantial
challenge (62, 63).
As little is known regarding the incidence of isoniazid-associated
hepatitis in HIV-infected African patients given both isoniazid
preventive therapy (IPT) and antiretroviral therapy, Tedla and
colleagues assessed the rate and risk factors for isoniazid-
associated hepatitis in persons living with HIV (64). A total
of 1,762 subjects who adhered to at least 4 months of IPT were
analyzed. Nineteen (1.1%) developed hepatitis probably or
possibly associated with isoniazid, including one death.
Seventy-four percent of the episodes occurred in Months 1
to 3. Antiretroviral therapy was received by 480 participants
but was not signicantly associated with isoniazid-hepatitis
(relative risk, 1.56). Although alcohol use did not escalate
the risk to achieve statistical signicance, meeting at least
one criterion from the CAGE (cutting down, annoyed, guilty,
eye opener) test for alcohol abuse allowed the increased risk to
182 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011
approach statistical signicance (relative risk, 2.37). Thus, the
observed rates of isoniazid-hepatitis were similar to published
data. Six months of IPT appeared to be relatively safe in the
largest cohort of African people living with HIV.
AERAS-402 is a novel TB vaccine designed to boost the pro-
tective immunity primed by BCG. Abel and colleagues embarked
on a study of the safety and immunogenicity of this new vaccine
in healthy BCG-vaccinated LTBI-free adults in Africa (65).
AERAS-402 was found to be well tolerated and no vaccine-
related serious adverse events were recorded. The vaccine
induced a robust CD4
1
T-cell response dominated by cells
coexpressing IFN-g, TNF-a, and IL-2. AERAS-402 also in-
duced a potent CD8
1
T-cell response, characterized by cells
expressing IFN-g and/or TNF-a, which persisted for the dura-
tion of the study. Such encouraging data would help to under-
pin the likely promising role of this vaccine.
Invariant natural killer T cells are important as they can rec-
ognize lipid antigens presented by the CD1 molecules, and may
have a role in the protective immunity of the host against myco-
bacteria (66). Sada-Ovalle and colleagues studied the ability of
a-galactosylceramideactivated invariant natural killer T cells
to suppress M. tuberculosis replication, using an in vitro cocul-
ture system, followed by assessing its potency in vivo, alone and
with isoniazid, in a murine model of TB. It was found that
a-galactosylceramide administration could improve the out-
come of murine TB, even when the animals were infected with
tubercle bacilli via the aerosol route. Furthermore, a combina-
tion of isoniazid and a-galactosylceramide treatment had syn-
ergistic potency. These results might have potential therapeutic
implications in patients with TB (66).
NONTUBERCULOUS MYCOBACTERIA
Studies have added to the wealth of information regarding the
NTM, especially those aimed at evaluating their epidemiology.
Andrejak and colleagues examined the incidence of pulmonary
colonization and disease due to NTM, and their associated prog-
nostic factors in Denmark (67). Of 1,282 adults (with 2,666
NTM-positive specimens), 26% of them had denite NTM dis-
ease, 19% possible disease, and 55% colonization only. Five-
year mortality after denite NTM disease was 40.1%. After
controlling for potential confounders, the 5-year mortality for
denite NTM disease was slightly higher than for NTM coloni-
zation (adjusted hazard ratio, 1.15). Mycobacterium xenopi was
found to be likely associated with worse prognosis (adjusted
hazard ratio, 1.51) than Mycobacterium avium complex. High
comorbidity level, age of at least 65 years, and male sex were
predictors of death. In Oregon in the United States, Winthrop
and colleagues determined the prevalence, clinical features, and
risk factors for NTM disease, and examined the predictive value
of the microbiological criteria of the American Thoracic Society
(ATS)/Infectious Disease Society of America (IDSA) case def-
inition for pulmonary NTM disease (68). Among 283 evaluable
subjects, 47% of them met ATS/IDSA pulmonary NTM disease
criteria for a minimum overall 2-year period prevalence of 8.6/
100,000 persons, and 20.4/100,000 in those at least 50 years of
age. Case subjects had a median age of 66 years, were frequently
female (59%), and had disease mostly due to M. avium complex
(88%). Cavitation, bronchiectasis, chronic obstructive pulmonary
disease, and immunosuppression were common (16 to 28%).
Eighty-six percent of patients who met the ATS/IDSA microbi-
ological criteria also meet the full ATS/IDSA disease criteria.
Thus, the microbiological criteria were found to be highly pre-
dictive of disease. Prevots and colleagues also studied the prev-
alence and trends for NTM lung disease at four geographically
diverse integrated health care delivery systems in the United
States (69). A total of 28,697 samples from 7,940 patients were
included in the analysis. Of these patients, 50 and 47% of them
were dened as possible and as denite cases, respectively. The
average annual site-specic prevalence ranged from 1.4 to 6.6 per
100,000. The prevalence, across sites, was 1.1- to 1.6-fold higher
among women relative to men. The prevalence of NTM lung
disease was increasing signicantly by 2.6 and 2.9% per year
among women and men, respectively. The increase was particu-
larly prominent among persons greater than or equal to 60 years
of age.
The treatment of NTM disease is often complicated by the
difculty in adhering to the prolonged therapy required, along-
side intolerance to the potentially toxic antimicrobial agents
used (3). Montes-Worboys and colleagues evaluated the use
of monocyte-derived dendritic cells, as a delivery vehicle, for
amikacin conjugated to uorescein isothiocyanate, into granu-
lomas formed in the tissues of mice infected with M. avium (70).
Quantitative uorescence was used to track intracellular uptake
of this modied antibiotic. The antimicrobial activity of the
modied amikacin was demonstrated to be comparable to the
unmodied aminoglycoside against M. avium. The investigators
found that the modied amikacin could be well delivered via
the dendritic cells into the granulomas in case of disseminated
mycobacteriosis. No increase in the markers of inammation,
such as monocyte chemoattractant protein-1, was observed.
These interesting ndings might have potential therapeutic
implications in the treatment of NTM disease.
References
1. World Health Organization. Global tuberculosis control. WHO report
2010. WHO/HTM/TB/2010.7. Geneva, Switzerland: 2010; World
Health Organization.
2. LoBue PA, Enarson DA, Thoen TC. Tuberculosis in humans and its
epidemiology, diagnosis and treatment in the United States. Int J
Tuberc Lung Dis 2010;14:12261232.
3. Taiwo B, Glassroth J. Nontuberculous mycobacterial lung diseases. In-
fect Dis Clin North Am 2010;24:769789.
4. Mukamolova GV, Turapov O, Malkin J, Woltmann G, Barer MR.
Resuscitation-promoting factors reveal an occult population of tu-
bercle bacilli in sputum. Am J Respir Crit Care Med 2010;181:174180.
5. Kaufmann SH. Future vaccination strategies against tuberculosis:
thinking outside the box. Immunity 2010;33:567577.
6. Chen X, Zhang M, Liao M, Graner MW, Wu C, Yang Q, Liu H, Zhou B.
Reduced Th17 response in patients with tuberculosis correlates with
IL-6R expression on CD4
1
T cells. Am J Respir Crit Care Med 2010;
181:734742.
7. Jeyanathan M, Mu J, McCormick S, Damjanovic D, Small CL, Shaler
CR, Kugathasan K, Xing Z. Murine airway luminal antituberculosis
memory CD8 T cells by mucosal immunization are maintained via
antigen-driven in situ proliferation, independent of peripheral T cell
recruitment. Am J Respir Crit Care Med 2010;181:862872.
8. Tena-Coki NG, Scriba TJ, Peteni N, Eley B, Wilkinson RJ, Andersen P,
Hanekom WA, Kampmann B. CD4 and CD8 T-cell responses to
mycobacterial antigens in African children. Am J Respir Crit Care
Med 2010;182:120129.
9. Hougardy JM, Schepers K, Place S, Drowart A, Lechevin V, Verscheure
V, Debrie AS, Doherty TM, Van Vooren JP, Locht C, et al. Heparin-
binding-hemagglutinin-induced IFN-g release as a diagnostic tool for
latent tuberculosis. PLoS One 2007;2:e926.
10. Place S, Verscheure V, de San N, Hougardy JM, Schepers K, Dirix V,
Dediste A, Michel O, Drowart A, Allard SD, et al. Heparin-binding,
hemagglutinin-specic IFN-g synthesis at the site of infection during
active tuberculosis in humans. Am J Respir Crit Care Med 2010;182:
848854.
11. Kagina BM, Abel B, Scriba TJ, Hughes EJ, Keyser A, Soares A,
Gamieldien H, Sidibana M, Hatherill M, Gelderbloem S, et al. other
members of the South African Tuberculosis Vaccine Initiative. Specic
T cell frequency and cytokine expression prole do not correlate with
protection against tuberculosis after bacillus Calmette-Guerin vacci-
nation of newborns. Am J Respir Crit Care Med 2010;182:10731079.
Pulmonary, Sleep, and Critical Care Updates 183
12. Smith SG, Lalor MK, Gorak-Stolinska P, Blitz R, Beveridge NE, Worth
A, McShane H, Dockrell HM. Mycobacterium tuberculosis PPD
induced immune biomarkers measurable in vitro following BCG
vaccination of UK adolescents by multiplex bead array and intra-
cellular cytokine staining. BMC Immunol 2010;11:35.
13. Moller M, Flachsbart F, Till A, Thye T, Horstmann RD, Meyer CG,
Osei I, van Helden PD, Hoal EG, Schreiber S, et al. A functional
haplotype in the 39 untranslated region of TNFRSF1B is associated
with tuberculosis in two African populations. Am J Respir Crit Care
Med 2010;181:388393.
14. Solovic I, Sester M, Gomez-Reino JJ, Rieder HL, Ehlers S, Milburn HJ,
Kampmann B, Hellmich B, Groves R, Schreiber S, et al. The risk of
tuberculosis related to tumour necrosis factor antagonist therapies:
a TBNET consensus statement. Eur Respir J 2010;36:11851206.
15. Horsburgh CR Jr, ODonnell M, Chamblee S, Moreland JL, Johnson J,
Marsh BJ, Narita M, Johnson LS, von Reyn CF. Revisiting rates of
reactivation tuberculosis: a population-based approach. Am J Respir
Crit Care Med 2010;182:420425.
16. ODonnell MR, Chamblee S, von Reyn CF, Ellerbrock TV, Johnson J,
Marsh BJ, Moreland JD, Narita M, Pedrosa M, Johnson LS, et al.
Racial disparities in primary and reactivation tuberculosis in a rural
community in the southeastern United States. Int J Tuberc Lung Dis
2010;14:733740.
17. Erkens CG, Kamphorst M, Abubakar I, Bothamley GH, Chemtob D,
Haas W, Migliori GB, Rieder HL, Zellweger JP, Lange C. Tuber-
culosis contact investigation in low prevalence countries: a European
consensus. Eur Respir J 2010;36:925949.
18. Hirsch-Moverman Y, Bethel J, Colson PW, Franks J, El-Sadr W. Pre-
dictors of latent tuberculosis infection treatment completion in the
United States: an inner city experience. Int J Tuberc Lung Dis 2010;
14:11041111.
19. Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D,
Bossink A, Magdorf K, Ho lscher C, Kampmann B, et al. TBNET.
LTBI: latent tuberculosis infection or lasting immune responses to M.
tuberculosis? A TBNET consensus statement. Eur Respir J 2009;33:
956973.
20. Arshad S, Bavan L, Gajari K, Paget SN, Baussano I. Active screening at
entry for tuberculosis among new immigrants: a systematic review and
meta-analysis. Eur Respir J 2010;35:13361345.
21. Kik SV, Franken WP, Mensen M, Cobelens FG, Kamphorst M, Arend
SM, Erkens C, Gebhard A, Borgdorff MW, Verver S. Predictive value
for progression to tuberculosis by IGRA and TST in immigrant
contacts. Eur Respir J 2010;35:13461353.
22. Mor Z, Lerman Y, Leventhal A. Pre-immigration screening for pulmo-
nary tuberculosis. Eur Respir J 2009;33:701702.
23. Klinkenberg E, Manissero D, Semenza JC, Verver S. Migrant tubercu-
losis screening in the EU/EEA: yield, coverage and limitations. Eur
Respir J 2009;34:11801189.
24. Middelkoop K, Bekker LG, Myer L, Whitelaw A, Grant A, Kaplan G,
McIntyre J, Wood R. Antiretroviral program associated with reduc-
tion in untreated prevalent tuberculosis in a South African township.
Am J Respir Crit Care Med 2010;182:10801085.
25. World Health Organization. Treatment of tuberculosis: Guidelines,
4th ed. WHO/HTM/TB2009.420. Geneva, Switzerland: 2010; World
Health Organization.
26. Gandhi NR, Shah NS, Andrews JR, Vella V, Moll AP, Scott M,
Weissman D, Marra C, Lalloo UG, Friedland GH; Tugela Ferry Care
and Research (TFCARES) Collaboration. HIV coinfection in multi-
drug- and extensively drug-resistant tuberculosis results in high early
mortality. Am J Respir Crit Care Med 2010;181:8086.
27. King L, Munsiff SS, Ahuja SD. Achieving international targets for tu-
berculosis treatment success among HIV-positive patients in New
York City. Int J Tuberc Lung Dis 2010;14:16131620.
28. Dheda K, Shean K, Zumla A, Badri M, Streicher EM, Page-Shipp L,
Willcox P, John MA, Reubenson G, Govindasamy D, et al. Early
treatment outcomes and HIV status of patients with extensively drug-
resistant tuberculosis in South Africa: a retrospective cohort study.
Lancet 2010;375:17981807.
29. Migliori GB, Sotgiu G. XDR tuberculosis in South Africa: old questions,
new answers. Lancet 2010;375:17601761.
30. Shin SS, Keshavjee S, Gelmanova IY, Atwood S, Franke MF, Mishustin
SP, Strelis AK, Andreev YG, Pasechnikov AD, Bamashov A, et al.
Development of extensively drug-resistant tuberculosis during multidrug-
resistant tuberculosis treatment. Am J Respir Crit Care Med 2010;182:
426432.
31. Kim DH, Kim HJ, Park SK, Kong SJ, Kim YS, Kim TH, Kim EK, Lee
KM, Lee SS, Park JS, et al. Treatment outcomes and survival based on
drug resistance patterns in multidrug-resistant tuberculosis. Am J
Respir Crit Care Med 2010;182:113119.
32. Migliori GB, Besozzi G, Girardi E, Kliiman K, Lange C, Toungoussova
OS, Ferrara G, Cirillo DM, Gori A, Matteelli A, et al. SMIRA/
TBNET Study Group. Clinical and operational value of the exten-
sively drug-resistant tuberculosis denition. Eur Respir J 2007;30:623
626.
33. Sotgiu G, Ferrara G, Matteelli A, Richardson MD, Centis R, Ruesch-
Gerdes S, Toungoussova O, Zellweger JP, Spanevello A, Cirillo D,
et al Epidemiology and clinical management of XDR-TB: a system-
atic review by TBNET. Eur Respir J 2009;33:871881.
34. Migliori GB, Richardson MD, Lange C. Of blind men and elephants:
making sense of extensively drug-resistant tuberculosis. Am J Respir
Crit Care Med 2008;178:10001001.
35. Baussano I, Nunn P, Williams B, Pivetta E, Bugiani M, Scano F.
Tuberculosis among health care workers. Emerg Infect Dis 2011;17:
488494.
36. ODonnell MR, Jarand J, Loveday M, Padavatchi N, Zelnick J, Weiner
L, Naidoo K, Master I, Osburn G, Kvasnovsky C, et al High incidence
of hospital admissions with multidrug-resistant and extensively drug-
resistant tuberculosis among South African health care workers. Ann
Intern Med 2010;153:516522.
37. van Zyl Smit RN, Pai M, Yew WW, Leung CC, Zumla A, Bateman ED,
Dheda K. Global lung health: the colliding epidemics of tuberculosis,
tobacco smoking, HIV and COPD. Eur Respir J 2010;35:2733.
38. Slama K, Chiang CY, Hinderaker SG, Bruce N, Vedal S, Enarson DA.
Indoor solid fuel combustion and tuberculosis: is there an association?
Int J Tuberc Lung Dis 2010;14:614.
39. Kim SH, Choi SJ, Kim HB, Kim NJ, Oh MD, Choe KW. Diagnostic
usefulness of a T-cell based assay for extrapulmonary tuberculosis.
Arch Intern Med 2007;167:22552259.
40. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K;
IGRA Expert Committee; Centers for Disease Control and Pre-
vention (CDC). Updated guidelines for using interferon gamma re-
lease assays to detect Mycobacterium tuberculosisinfectionUnited
States, 2010.MMWR Recomm Rep 2010;59:125.
41. Patel VB, Singh R, Connolly C, Coovadia Y, Peer AK, Parag P,
Kasprowicz V, Zumla A, Ndungu T, Dheda K. Cerebrospinal T-cell
responses aid in the diagnosis of tuberculous meningitis in a human
immunodeciency virus- and tuberculosis-endemic population. Am J
Respir Crit Care Med 2010;182:569577.
42. Metcalfe JZ, Cattamanchi A, Vittinghoff E, Ho C, Grinsdale J, Hopewell
PC, Kawamura LM, Nahid P. Evaluation of quantitative IFN-g re-
sponse for risk stratication of active tuberculosis suspects. Am J Respir
Crit Care Med 2010;181:8793.
43. Leung CC, Yam WC, Yew WW, Ho PL, Tam CM, Law WS, Au KF,
Tsui PW. T-SPOT.TB outperforms tuberculin skin test in predicting
tuberculosis disease. Am J Respir Crit Care Med 2010;182:834840.
44. World Health Organization. Strategic and Technical Advisory Group for
Tuberculosis (STAG-TB), Report of the Tenth Meeting, September
2729, 2010. WHO/HTM/TB/2010.18. Geneva, Switzerland: 2010;
World Health Organization.
45. Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F,
Allen J, Tahirli R, Blakemore R, Rustomjee R, et al. Rapid molecular
detection of tuberculosis and rifampin resistance. N Engl J Med 2010;
363:10051015.
46. Swaminathan S, Narendran G, Venkatesan P, Iliayas S, Santhanakrishnan
R, Menon PA, Padmapriyadarsini C, Ramachandran R, Chinnaiyan P,
Suhadev M, et al. Efcacy of a 6-month versus 9-month intermittent
treatment regimen in HIV-infected patients with tuberculosis:
a randomized clinical trial. Am J Respir Crit Care Med 2010;181:
743751.
47. Vernon A. A trial involving HIV-tuberculosis in India: the minute par-
ticulars. Am J Respir Crit Care Med 2010;181:652654.
48. Yew WW, Lange C, Leung CC. Treatment of tuberculosis: update 2010.
Eur Respir J 2011;37:441462.
184 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011
49. Chiang CY, Schaaf HS. Management of drug-resistant tuberculosis. Int J
Tuberc Lung Dis 2010;14:672682.
50. Caminero JA. Multidrug-resistant tuberculosis: epidemiology, risk fac-
tors and case nding. Int J Tuberc Lung Dis 2010;14:382390.
51. Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for
multidrug-resistant and extensively drug-resistant tuberculosis. Lan-
cet Infect Dis 2010;10:621629.
52. Leimane V, Dravniece G, Riekstina V, Sture I, Kammerer S, Chen P,
Skenders G, Holtz TH. Treatment outcome of multidrug/extensively
drug-resistant tuberculosis in Latvia, 20002004. Eur Respir J 2010;36:
584593.
53. Migliori GB, Eker B, Richardson MD, Sotgiu G, Zellweger JP, Skrahina
A, Ortmann J, Girardi E, Hoffmann H, Besozzi G, et al. TBNET
Study Group. A retrospective TBNET assessment of linezolid safety,
tolerability and efcacy in MDR-TB. Eur Respir J 2009;34:387393.
54. Yew WW, Chang KC, Chau CH. What is the optimal dosage of linezolid
in treatment of complicated multidrug-resistant tuberculosis. Eur
Respir J 2009;34:14921494.
55. Anger HA, Dworkin F, Sharma S, Munsiff SS, Nilsen DM, Ahuja SD.
Linezolid use for treatment of multidrug-resistant and extensively
drug-resistant tuberculosis, New York City, 200006. J Antimicrob
Chemother 2010;65:775783.
56. Schecter GF, Scott C, True L, Raftery A, Flood J, Mase S. Linezolid in
the treatment of multidrug-resistant tuberculosis. Clin Infect Dis 2010;
50:4955.
57. Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P,
Rieder HL. Short, highly effective, and inexpensive standardized
treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care
Med 2010;182:684692.
58. Mitnick C, Horsburgh CR Jr. Encouraging news for multidrug-resistant
tuberculosis treatment. Am J Respir Crit Care Med 2010;182:1337
1338.
59. Chang KC, Leung CC, Yew WW, Lau TY, Leung WM, Tam CM, Lam
HC, Tse PS, Wong MY, Lee SW, et al. Newer uoroquinolones for
treating respiratory infection: do they mask tuberculosis? Eur Respir J
2010;35:606613.
60. World Health Organization. Guidelines for the programmatic manage-
ment of drug-resistant tuberculosis. WHO/HTM/TB/2008.402. Ge-
neva, Switzerland: 2008; World Health Organization.
61. Oxlade O, Schwartzman K, Pai M, Heymann J, Benedetti A, Royce S,
Menzies D. Predicting outcomes and drug resistance with stand-
ardised treatment of active tuberculosis. Eur Respir J 2010;36:870
877.
62. Nunn A. What is the role of clinical trials for the treatment of tuber-
culosis and what are the alternatives? Int J Tuberc Lung Dis 2010;14:
380381.
63. Lienhardt C, Davies G. Methodological issues in the design of clinical
trials for the treatment of multidrug-resistant tuberculosis: challenges
and opportunities. Int J Tuberc Lung Dis 2010;14:528537.
64. Tedla Z, Nyirenda S, Peeler C, Agizew T, Sibanda T, Motsamai O,
Vernon A, Wells CD, Samandari T. Isoniazid-associated hepatitis and
antiretroviral drugs during tuberculosis prophylaxis in HIV-infected
adults in Botswana. Am J Respir Crit Care Med 2010;182:278285.
65. Abel B, Tameris M, Mansoor N, Gelderbloem S, Hughes J, Abrahams
D, Makhethe L, Erasmus M, de Kock M, van der Merwe L, et al. The
novel tuberculosis vaccine, AERAS-402, induces robust and poly-
functional CD4
1
and CD8
1
T cells in adults. Am J Respir Crit Care
Med 2010;181:14071417.
66. Sada-Ovalle I, Skold M, Tian T, Besra GS, Behar SM. a-Galactosylceramide
as a therapeutic agent for pulmonary Mycobacterium tuberculosis in-
fection. Am J Respir Crit Care Med 2010;182:841847.
67. Andrejak C, Thomsen VO, Johansen IS, Riis A, Beneld TL, Duhaut P,
Sorensen HT, Lescure FX, Thomsen RW. Nontuberculous pulmonary
mycobacteriosis in Denmark: incidence and prognostic factors. Am J
Respir Crit Care Med 2010;181:514521.
68. Winthrop KL, McNelley E, Kendall B, Marshall-Olson A, Morris C,
Cassidy M, Saulson A, Hedberg K. Pulmonary nontuberculous my-
cobacterial disease prevalence and clinical features: an emerging
public health disease. Am J Respir Crit Care Med 2010;182:977982.
69. Prevots DR, Shaw PA, Strickland D, Jackson LA, Raebel MA, Blosky
MA, Montes de Oca R, Shea YR, Seitz AE, Holland SM, et al.
Nontuberculous mycobacterial lung disease prevalence at four in-
tegrated health care delivery systems. Am J Respir Crit Care Med
2010;182:970976.
70. Montes-Worboys A, Brown S, Regev D, Bellew BF, Mohammed KA,
Faruqi I, Sharma P, Moudgil B, Antony VB. Targeted delivery of ami-
kacin into granulomas. Am J Respir Crit Care Med 2010;182:15461553.
Pulmonary, Sleep, and Critical Care Updates 185