Abstract

Background. Shortened regimens for treatment of pulmonary tuberculosis (TB) are urgently needed to facilitate its global eradication. Prolonged treatment is presently required to prevent relapse, which is thought to arise from persisting foci of semidormant infection contained within granulomas.

Methods. The medical literature was reviewed to identify clinical trials of adjuvant TB immunotherapy, as well as other studies of the relationship between immune status and TB relapse or reactivation.

Results. Four studies of therapeutic interferon indicated its inability to effectively augment the mycobactericidal capacity of lung macrophages. One randomized, placebo-controlled trial of therapeutic interleukin-2 found that it delayed the microbiologic response to treatment, whereas 2 controlled trials of anti—tumor necrosis factor (TNF) therapies (high-dose prednisolone and etanercept [a soluble TNF receptor]) found that these interventions significantly accelerated the response to treatment. Four retrospective studies were identified in which the response to TB therapy was accelerated and/or the relapse risk was reduced in persons with human immunodeficiency virus coinfection; one study reported that immune reconstitution syndrome due to use of antiretroviral therapy was associated with increased risk of relapse. Several studies indicated that granulomas may be efficiently targeted and disrupted by the anti-TNF antibody infliximab, apparently because of its ability to bind to cell-surface TNF and to induce apoptosis in TNF-expressing cells.

Conclusions. These findings support the hypothesis that the granulomatous host response to TB may paradoxically protect sequestered mycobacteria from administered anti-TB therapy and that treatment may be improved by therapeutic disruption of granulomas. Clinical trials to test this hypothesis are warranted.

Granulomas, the hallmark of the host response to mycobacterial infection, represent a strategy to physically contain infections that cannot otherwise be eradicated by host defenses (figure 1). The sequential recruitment of cells to the site of Mycobacterium tuberculosis infection forms a physical barrier to mycobacterial dissemination and creates a hostile microenvironment in which oxygen tension, pH, and micronutrient supply are all likely reduced. Faced with this environment, mycobacteria undergo profound alterations in metabolism, biosynthesis, and replication. This adaptation forms the basis of clinical latency in tuberculosis. Although the elucidation of the biology of these sequestered, semidormant bacilli has become a critical area of research in tuberculosis, their paucity makes direct study in vivo problematic. Therefore, most research on this question has been performed using in vitro models, such as oxygen deprivation or intracellular growth in macrophages [1–9]. These models have identified metabolic pathways (e.g., the glyoxylate shunt pathway) and 2-component regulatory systems (Rv3133c/DosR) required for mycobacterial persistence.

Figure 1

Tuberculous lung granuloma. The central region of multinucleated giant cells, mycobacteria, and necrotic debris are surrounded by concentric rings of tightly apposed epithelioid cells and lymphocytes, with smaller numbers of neutrophils, plasma cells, and fibroblasts.

Figure 1

Tuberculous lung granuloma. The central region of multinucleated giant cells, mycobacteria, and necrotic debris are surrounded by concentric rings of tightly apposed epithelioid cells and lymphocytes, with smaller numbers of neutrophils, plasma cells, and fibroblasts.

Karakousis et al. [10] recently reported a study of the biology of dormancy using artificial granulomas that comprised hollow, M. tuberculosis—containing, semipermeable microfibers implanted subcutaneously in mice. The fibers, which permit diffusion of nutrients and soluble mediators but exclude intact cells, rapidly become surrounded by macrophages and lymphocytes. The model requires intact cellular host immune responses; it is of particular interest, because its extracellular bacillary localization may mirror that of human tuberculosis. Karakousis and colleagues found that the mycobacteria contained within these lesions quickly adapted to the altered environment, showing stationary colony-forming unit (CFU) counts, decreased metabolism, altered gene-expression profiles (including activation of Rv3133c/DosR), and decreased susceptibility to the bactericidal effects of isoniazid. Isoniazid is thought to mainly kill metabolically active, replicating bacilli, during the early phase of therapy. As a consequence, it has little sterilizing effect, which has been defined in clinical trials as the ability to shorten therapy and prevent relapse. This is therefore the first experimental model in which granulomas interfered with sterilization.

Treatment of active tuberculosis presently requires 6 months of multidrug treatment. Relapses occur if patient adherence is inadequate. Even after optimal treatment, relapses occur in ∼5% of cases. It is believed that the requirement for prolonged treatment reflects the relative inactivity of current drugs against semidormant organisms contained in granulomas; however, this hypothesis has never explicitly been tested. The long duration of treatment poses a major obstacle to global tuberculosis eradication. For this reason, the development of new treatments capable of shortening the duration of tuberculosis treatment is recognized as a major objective of tuberculosis drug discovery [11].

The design of clinical trials to test new treatments poses several challenges. The existence of effective but inefficient standard “short-course” therapy makes conventional trials prolonged, large, and costly. As a result, most studies of adjuvant tuberculosis immunotherapy have adopted an alternative strategy, testing new treatments in patients with multidrug resistant (MDR) disease or substituting surrogate markers that indicate relapse risk (such as 2-month sputum culture status or time to conversion of sputum culture results) as the main outcome measure. Delayed sputum culture conversion and a reduced rate of decline in log sputum counts (in CFUs) during the first month of treatment are recognized indicators of increased relapse risk in patients with tuberculosis [12–14]. However, the use of these end points has the potential disadvantage that they require that the experimental treatment be administered during the initial phase of tuberculosis therapy.

Clinical Trials of Adjunctive Immunotherapy

IFN-γ. IFN-γ is essential for antimycobacterial host defenses [15]. In mice, IFN-γ increases the mycobactericidal capacity of macrophages by promoting the production of reactive nitrogen intermediates, such as nitric oxide [16, 17]. The first trial of therapeutic IFN-γ in patients with tuberculosis without overt defects of IFN-γ production or responsiveness was reported in 1997 by Condos et al. [18]. In this uncontrolled study, 500 µg of IFN-γ was administered 3 times per week by aerosol to 5 patients with MDR tuberculosis in addition to their previous therapy. The study found that sputum smear results became negative and that the number of CFUs tended to decrease. Three similar subsequent studies by other investigators that differed in IFN type, dose, and route of administration failed to meet even this modest measure of success (table 1) [19–21]. The only randomized, placebo-controlled, multicenter trial of inhaled adjunctive IFN-γ for MDR tuberculosis was initiated by InterMune in 2000 [22]. The trial was halted prematurely because of a lack of efficacy; its findings have never been published. Subsequent research has indicated that IFN-γ–induced genes, such as IP-10 and iNOS, are already upregulated in the lung in patients with tuberculosis and that therapeutic aerosol IFN-γ has relatively little additional effect [23]. These findings indicate that the modest mycobactericidal capacity of lung macrophages cannot effectively be augmented by therapeutic IFN.

Table 1

Clinical trials of adjunctive IFN for treatment of multidrug-resistant pulmonary tuberculosis.

Table 1

Clinical trials of adjunctive IFN for treatment of multidrug-resistant pulmonary tuberculosis.

IL-2. IL-2 promotes T cell replication and is essential for cellular immune function and granuloma formation. In 1997, a small, unblinded study of 2 low-dose IL-2 regimens (daily or in 5-day “pulses”) in patients with MDR tuberculosis found that the daily regimen appeared to decrease sputum acid-fast bacilli counts [24]. On the basis of this preliminary observation, a randomized, double-blind, placebo-controlled trial of the effect of IL-2 on conversion of sputum culture results was conducted by the Case Western Reserve University Tuberculosis Research Unit (Cleveland, OH) with 110 Ugandan, HIV-uninfected patients with drug-susceptible tuberculosis [25]. IL-2 or placebo was administered twice daily for the first month of standard therapy. Contrary to expectations, the study found significant delays in clearance of viable M. tuberculosis CFU and conversion of sputum culture results in the IL-2 treatment arm (figure 2). This report was the first clinical indication of possible antagonism during combined chemotherapy and immunotherapy for tuberculosis.

Figure 2

Deleterious effect of IL-2 on sputum microbiologic end points in a study of 110 subjects with pulmonary tuberculosis. Adapted from [25]. CFU, colony-forming units.

Figure 2

Deleterious effect of IL-2 on sputum microbiologic end points in a study of 110 subjects with pulmonary tuberculosis. Adapted from [25]. CFU, colony-forming units.

TNF. TNF, like IFN-γ, is essential for host defenses against tuberculosis. TNF is a potent proinflammatory cytokine that is expressed by macrophages and T cells, first as a cell-surface—associated cytokine, and then, after cleavage of membrane-anchoring domains, as a soluble homotrimer [26, 27]. TNF stimulates the release of inflammatory cytokines, endothelial adhesion molecules, and chemokines.

TNF plays a central role in the host response to M. tuberculosis. Monocytes express TNF after phagocytosis of mycobacteria or after stimulation by mycobacterial proteins or glycolipids [26, 28–30]. TNF is expressed at the site of disease in patients with newly diagnosed tuberculosis [31–33]. TNF levels increase shortly after initiation of antituberculosis therapy [33], possibly because of a release of microbial constituents that stimulate TNF production [34–36]. Levels subsequently decrease as the bacillary burden is reduced by treatment [31].

TNF is essential for the formation and maintenance of granulomas. Neutralization of TNF in experimental animals interferes with the early recruitment of inflammatory cells to the site of M. tuberculosis infection and inhibits the orderly formation of granulomas [37, 38]. In addition, TNF blockade also reduces the microbicidal activity of macrophages and NK cells [39, 40]. As a result, animals deficient in TNF are highly susceptible to granulomatous infections [41]. Recent studies also indicate that the risk of tuberculosis is increased several-fold in individuals with polymorphisms in TNF-promoter regions [42], and the risk may increase by as much as 20-fold in patients treated with TNF antagonists (see “Can Granulomas Be Targeted Efficiently?,” below).

Two controlled clinical trials have examined the effects of potent immunosuppressive and/or anti-TNF therapies on microbiologic outcomes in tuberculosis. Both were conducted with HIV-1—infected patients who had relatively preserved tuberculosis immune responses (based on the presence of high CD4 cell counts and cavitary lung disease). The trials shared a single placebo control arm (for tuberculosis therapy only). Their main objective was to examine the role of TNF in the acceleration of HIV disease progression due to tuberculosis; as such, their main end points were CD4 cell count and plasma HIV RNA load. However, both studies prospectively collected clinical and microbiologic data as indicators of safety.

Etanercept (soluble TNF receptor). A phase I study examined the effects of etanercept (25 mg sc twice weekly for 8 doses) given to 16 subjects, starting on day 4 of tuberculosis treatment [43]. Responses were compared with those for 42 CD4 cell count—matched control subjects. Conversion of sputum culture results occurred a median of 7 days earlier in the etanercept arm (P = .04) (figure 3). Etanercept was well tolerated. There were no serious opportunistic infections. CD4 cell counts increased by 96 cells/µL after 1 month of etanercept treatment (P = .1, for comparison with control subjects); this effect may have been associated with inhibition of apoptosis [44, 45]. The etanercept arm also showed trends toward superior resolution of lung infiltrates, closure of lung cavities, improvement in performance score, and weight gain; these findings approached statistical significance, despite the small number of treated subjects.

Figure 3

Acceleration of conversion of sputum culture results associated with receipt of etanercept and high-dose methylprednisolone (2.75 mg/kg/day) in patients with pulmonary tuberculosis. Each symbol represents an individual subject. Results for etanercept and high-dose methylprednisolone treatments differed from those for control subjects by Kaplan-Meier analysis (P = .04 and .001, respectively). Adapted from [43, 46].

Figure 3

Acceleration of conversion of sputum culture results associated with receipt of etanercept and high-dose methylprednisolone (2.75 mg/kg/day) in patients with pulmonary tuberculosis. Each symbol represents an individual subject. Results for etanercept and high-dose methylprednisolone treatments differed from those for control subjects by Kaplan-Meier analysis (P = .04 and .001, respectively). Adapted from [43, 46].

High-dose methylprednisolone. A substantially greater microbiologic effect was observed a phase II study reported by Mayanja-Kizza et al. [46] in which 189 subjects who were treated with prednisolone (2.75 mg/kg/day) or placebo during the first month of standard tuberculosis therapy. The prednisolone dosage had been selected on the basis of a phase I study indicating that it reduced the rate of tuberculosis-stimulated TNF production ex vivo by one-half. The daily dose was tapered to 0 mg/kg during the second month; the average subject received a cumulative dose of >6500 mg. Although there is extensive experience with the use of corticosteroids to ameliorate symptoms of tuberculosis, no previous studies have examined the microbiologic effects of doses of this magnitude. Unexpectedly, one-half of prednisolone-treated subjects had conversion of sputum culture results to negative after 1 month of treatment, compared with 10% of subjects in the placebo arm (P = .001) (figure 3). This effect was of greater magnitude than that observed in the landmark study in which the addition of rifampin to a 6-month regimen of streptomycin and isoniazid reduced the relapse rate from 29% to 2% and to increase the 2-month sputum culture conversion rate from 49% to 69% [47]. The effect of prednisolone therapy was not due to reduced sputum production, which decreased similarly during treatment in both study arms. There were no serious opportunistic infections. However, prednisolone-treated subjects were more likely to experience other early serious adverse events, including edema, hyperglycemia, electrolyte disturbances, and severe hypertension.

Two other prospective, randomized trials of adjunctive corticosteroids administered at lower doses have observed similar, albeit smaller, effects on the kinetics of conversion of sputum culture results [48, 49]. A third trial found no effect [50]. There have been no reports of deleterious effects of corticosteroids on microbiologic outcomes in patients with tuberculosis.

Do Granulomas Interfere with Sterilization?

The incidence of tuberculosis is elevated among patients who are treated with prednisone or etanercept [51, 52], indicating that these treatments interfere with granuloma formation and/or maintenance in humans, as they do in experimental animals. Yet, paradoxically, when administered to patients with active tuberculosis, these treatments accelerate the microbiologic response to therapy, an effect otherwise associated with decreased risk of relapse. Can these trials then be broadly interpreted as indicating a potential therapeutic benefit conferred by adjunctive antigranuloma therapy in tuberculosis?

Several caveats are appropriate before this question can be answered definitively. No surrogate markers have yet been fully validated as predictors of tuberculosis relapse or indicators of the effectiveness of new tuberculosis therapies. Moreover, experience with these markers during conventional antituberculosis therapy may not necessarily predict the experience during immunotherapy. In mice, neither prior bacille Calmette-Guérin (BCG) vaccination nor concurrent corticosteroid therapy significantly affected the response to antituberculosis therapy [53, 54]. The mouse may be a poor model in which to study the therapeutic effects of granuloma disruption, however, because murine tuberculosis granulomas are loose collections of activated and epithelioid macrophages and lymphocytes that lack the multinucleated giant cells, necrosis, caseation, and cavitation characteristic of human pathology [55, 56]. In humans, cavitary disease is associated with delayed sputum culture conversion and increased risk of subsequent relapse [14].

Tuberculosis granulomas in the guinea pig and rabbit more closely resemble those of humans. Prior vaccination with BCG reduces the bactericidal activity of isoniazid in the guinea pig, whereas it does not in the mouse [53]. No analogous studies have yet examined the effects of corticosteroids or TNF blockers during tuberculosis therapy in the guinea pig. Some TNF blockers (including infliximab) are highly specific for human TNF [57]. The lack of highly potent, specific TNF antagonists for the guinea pig or rabbit limits the present role of these animal models in addressing this question.

AIDS, like high-dose corticosteroid therapy, profoundly inhibits the granulomatous response to mycobacterial infection. Unlike iatrogenic immunosuppression, immune dysfunction due to AIDS may either worsen because of HIV disease progression or improve after initiation of antiretroviral therapy, thus complicating the analysis of its effects on antituberculosis therapy. Only 1 prospective study of the influence of HIV infection on tuberculosis relapse in the absence of antiretroviral therapy has been reported [58]. In it, Sonnenberg and colleagues studied recurrent tuberculosis in a cohort of 326 South African miners with and without HIV infection, using restriction fragment—length polymorphism analysis to distinguish true relapses from disease due to reinfection. Although the total rate of recurrence was increased by HIV-1 infection, strain typing revealed that these cases were primarily due to reinfection (the rate of which increased 18-fold) rather than true relapse (the rate of which was reduced by one-half).

Several additional studies using surrogate markers support the observation that HIV infection may improve the effectiveness of antituberculous therapy. A combined analysis of Tuberculosis Trials Consortium Studies 22 and 23 indicates that 2-month sputum culture conversion rates for HIV-infected patients were superior to those for noninfected patients (94% vs. 78%; P < .05) [59]. Two small treatment trials using other sputum surrogate markers concur with this observation [13, 60]. Lastly, a large, multicenter study of tuberculosis chemotherapy for HIV-infected persons initiated jointly by AIDS Clinical Trials Group and the Terry Beirn Community Programs for Clinical Research on AIDS in the pre-HAART era found that >95% of subjects had conversion of sputum culture results to negative by week 8 of the study and that the main end point (relapse) could not be assessed because rates were unexpectedly low in all treatment arms [61].

Some patients who begin receiving combined treatment for AIDS and tuberculosis experience a particularly rapid recovery of tuberculosis-specific immune functions. This syndrome, which has been termed “immune reconstitution inflammatory syndrome” (IRIS), occurs most often in patients with far-advanced AIDS who have both pulmonary and extrapulmonary tuberculosis. Patients with IRIS typically are anergic prior to starting antiretroviral therapy but rapidly have conversion to strongly positive tuberculin skin test results as the syndrome evolves. They experience “paradoxical” reactions to treatment (i.e., worsened fever, pulmonary infiltrates, lymphadenopathy, etc.) due to immune reconstitution. One study by Narita et al. [62] found a 6-fold increased risk of subsequent tuberculosis relapse in patients who experienced IRIS during early tuberculosis treatment.

Can Granulomas be Targeted Efficiently?

Formal testing of the hypothesis that granuloma disruption accelerates the response to tuberculosis therapy will require an efficient means to target and disrupt human granulomas. Experience with prednisolone indicates that corticosteroids may not be the best intervention with which to test this hypothesis, because the high doses that appear to be required to produce a therapeutic effect are associated with a substantial risk of early serious adverse events [46]. This safety profile likely will prevent high-dose prednisolone therapy from becoming a first-line treatment, even if other aspects of therapeutic efficacy in tuberculosis could be established.

The treatment of other chronic inflammatory conditions, such as rheumatoid arthritis, has been transformed in the past decade by the development of targeted therapies that block specific aspects of the inflammatory cascade, such as TNF, while avoiding the recognized toxicities of high-dose corticosteroid therapy. Several studies indicate that infliximab (anti-TNF antibody), may be highly effective in disrupting established granulomas, because reactivation of latent granulomatous infections has been one of its most frequently reported serious adverse effects. Tuberculosis occurs at a rate of 95 cases per 100,000 person-years during the first 90 days of infliximab therapy, compared with 11 cases per 100,000 person-years for etanercept therapy and 5 cases per 100,000 person-years in the United States as a whole [63, 64]. The risk posed by infliximab subsequently decreases (consistent with reactivation of preexisting latent infection), whereas that of etanercept does not (consistent with the inability to contain incident tuberculosis infection) [52]. Granulomatous infections other than tuberculosis are similarly more common among infliximab-treated patients [65–67].

Corresponding differences between infliximab and etanercept exist in their therapeutic indications. Only infliximab is effective for treatment of chronic granulomatous inflammatory diseases, such as Crohn disease, sarcoidosis, or Wegener granulomatosis [68–71]. In patients with Crohn disease, a single dose of infliximab can induce long-lasting remissions and closure of chronic enteric fistulas [72]. This effect is not readily explained by the pharmacokinetics of its binding to soluble TNF, but may rather reflect its capacity to induce apoptosis in activated monocytes and lymphocytes by binding to cell-surface TNF [73–76]. This mechanism, which presumably kills TNF-expressing cells that constitute granulomas, is presently the subject of ongoing research.

Infliximab has not yet been studied as adjunctive therapy for tuberculosis. For such a study to be performed safely and ethically, its design must ensure that subjects are not exposed to an undue risk of disseminated or uncontrolled mycobacterial infection. Such a study could only be conducted with fully drug-susceptible cases; indeed, in MDR cases, containment remains a viable alternative to eradication. The trials of etanercept and methylprednisolone described earlier indicate that other potent anti-inflammatory and anti-TNF treatments do not per se pose a significant risk to patients with pulmonary tuberculosis, even to those with HIV coinfection. This risk may be further reduced by delaying infliximab therapy until after the first week of treatment (at which time sputum CFU counts have decreased by nearly 2 log), initially testing subtherapeutic doses, monitoring blood cultures and clinical outcomes closely, and adding moxifloxacin to the treatment regimen. Unlike isoniazid and rifampin, the long serum half-life of moxifloxacin ensures that its levels remain greater than the MIC for M. tuberculosis throughout the dosing interval.

Other risks may also be considered. IRIS has been reported in infliximab-associated tuberculosis cases after withdrawal of infliximab [77]. Like patients with AIDS-associated IRIS, all patients with infliximab-associated IRIS had extrapulmonary and/or disseminated tuberculosis at the time of diagnosis; therefore, IRIS may be unlikely in patients with limited pulmonary disease. Nonetheless, monitoring for IRIS, with supplemental low-dose corticosteroids (or repeated infliximab administration), may be appropriate. These measures will reduce the anticipated risks posed by study participation to an acceptable level.

Summary

Although granulomas are an essential part of host defenses against mycobacterial infection, they appear, paradoxically, to protect M. tuberculosis bacilli during tuberculosis therapy. Additional studies of targeted disruption of granulomas are warranted to better understand granuloma biology, to inform drug discovery, and to test a new therapeutic approach in tuberculosis.

Acknowledgments

I wish to thank Drs. William Newman, Melissa Taggart, and Susan Wang (Louisiana State University Health Science Center, New Orleans) for providing the photomicrograph used in figure 1.

Potential conflicts of interest. R.S.W. has received research grant support from Wyeth Pharmaceuticals, to study the effects of TNF blockers on the in vitro expression of mycobacterial immunity, and from Immunex, to study the effects of etanercept involving a clinical trial in tuberculosis, and has served as a consultant for Amgen.

References

1
McKinney
JD
Honer zu
BK
Munoz-Elias
EJ
, et al.  . 
Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase
Nature
 , 
2000
, vol. 
406
 (pg. 
735
-
8
)
2
Dubnau
E
Fontán
F
Manganelli
R
Soares-Appel
S
Smith
I
Mycobacterium tuberculosis genes induced during infection of human macrophages
Infect Immun
 , 
2002
, vol. 
70
 (pg. 
2787
-
95
)
3
Dubnau
E
Smith
I
Mycobacterium tuberculosis gene expression in macrophages
Microbes Infect
 , 
2003
, vol. 
5
 (pg. 
629
-
37
)
4
Manganelli
R
Dubnau
E
Tyagi
S
Kramer
FR
Smith
I
Differential expression of 10 sigma factor genes in Mycobacterium tuberculosis
Mol Microbiol
 , 
1999
, vol. 
31
 (pg. 
715
-
24
)
5
Rodriguez
GM
Smith
I
Mechanisms of iron regulation in mycobacteria: role in physiology and virulence
Mol Microbiol
 , 
2003
, vol. 
47
 (pg. 
1485
-
94
)
6
Park
HD
Guinn
KM
Harrell
MI
, et al.  . 
Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis
Mol Microbiol
 , 
2003
, vol. 
48
 (pg. 
833
-
43
)
7
Sherman
DR
Voskuil
M
Schnappinger
D
Liao
R
Harrell
MI
Schoolnik
GK
Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha-crystallin
Proc Natl Acad Sci USA
 , 
2001
, vol. 
98
 (pg. 
7534
-
9
)
8
Voskuil
MI
Schnappinger
D
Visconti
KC
, et al.  . 
Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program
J Exp Med
 , 
2003
, vol. 
198
 (pg. 
705
-
13
)
9
Voskuil
MI
Visconti
KC
Schoolnik
GK
Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy
Tuberculosis (Edinb)
 , 
2004
, vol. 
84
 (pg. 
218
-
27
)
10
Karakousis
PC
Yoshimatsu
T
Lamichhane
G
, et al.  . 
Dormancy phenotype displayed by extracellular Mycobacterium tuberculosis within artificial granulomas in mice
J Exp Med
 , 
2004
, vol. 
200
 (pg. 
647
-
57
)
11
O'Brien
RJ
Scientific blueprint for tuberculosis drug development. Global Alliance for TB Drug Development
Tuberculosis
 , 
2001
, vol. 
81
 
Suppl 1
(pg. 
1
-
52
)
12
Mitchison
DA
Assessment of new sterilizing drugs for treating pulmonary tuberculosis by culture at 2 months [letter]
Am Rev Respir Dis
 , 
1993
, vol. 
147
 (pg. 
1062
-
3
)
13
Brindle
R
Odhiambo
J
Mitchison
DA
Serial counts of Mycobacterium tuberculosisin sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis
BMC Pulm Med
 , 
2001
, vol. 
1
 pg. 
2
 
14
Benator
D
Bhattacharya
M
Bozeman
L
, et al.  . 
Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial
Lancet
 , 
2002
, vol. 
360
 (pg. 
528
-
34
)
15
Jouanguy
E
Altare
F
Lamhamedi
S
, et al.  . 
Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection
N Engl J Med
 , 
1996
, vol. 
335
 (pg. 
1956
-
61
)
16
Flesch
I
Kaufmann
SH
Mycobacterial growth inhibition by interferon-gamma-activated bone marrow macrophages and differential susceptibility among strains of Mycobacterium tuberculosis
J Immunol
 , 
1987
, vol. 
138
 (pg. 
4408
-
13
)
17
Chan
J
Xing
Y
Magliozzo
RS
Bloom
BR
Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages
J Exp Med
 , 
1992
, vol. 
175
 (pg. 
1111
-
22
)
18
Condos
R
Rom
WN
Schluger
NW
Treatment of multidrug-resistant pulmonary tuberculosis with interferon-gamma via aerosol
Lancet
 , 
1997
, vol. 
349
 (pg. 
1513
-
5
)
19
Giosue
S
Casarini
M
Ameglio
F
, et al.  . 
Aerosolized interferon-alpha treatment in patients with multi-drug-resistant pulmonary tuberculosis
Eur Cytokine Netw
 , 
2000
, vol. 
11
 (pg. 
99
-
104
)
20
Suarez-Mendez
R
Garcia-Garcia
I
Fernandez-Olivera
N
, et al.  . 
Adjuvant interferon gamma in patients with drug-resistant pulmonary tuberculosis: a pilot study
BMC Infect Dis
 , 
2004
, vol. 
4
 pg. 
44
 
21
Koh
WJ
Kwon
OJ
Suh
GY
, et al.  . 
Six-month therapy with aerosolized interferon-gamma for refractory multidrug-resistant pulmonary tuberculosis
J Korean Med Sci
 , 
2004
, vol. 
19
 (pg. 
167
-
71
)
22
InterMune investor relations press release: InterMune enrolls first patient in phase III trial in multidrug-resistant tuberculosis
 , 
2000
 
Available at: http://www.hopkins-tb.org/news/7-31-2000.shtml. Accessed 18 May 2005
23
Raju
B
Hoshino
Y
Kuwabara
K
, et al.  . 
Aerosolized gamma interferon (IFN-gamma) induces expression of the genes encoding the IFN-gamma-inducible 10-kilodalton protein but not inducible nitric oxide synthase in the lung during tuberculosis
Infect Immun
 , 
2004
, vol. 
72
 (pg. 
1275
-
83
)
24
Johnson
BJ
Bekker
LG
Rickman
R
, et al.  . 
rhuIL-2 adjunctive therapy in multidrug resistant tuberculosis: a comparison of two treatment regimens and placebo
Tuber Lung Dis
 , 
1997
, vol. 
78
 (pg. 
195
-
203
)
25
Johnson
JL
Ssekasanvu
E
Okwera
A
, et al.  . 
Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis
Am J Respir Crit Care Med
 , 
2003
, vol. 
168
 (pg. 
185
-
91
)
26
Wallis
RS
Amir Tahmasseb
M
Ellner
JJ
Induction of interleukin 1 and tumor necrosis factor by mycobacterial proteins: the monocyte Western blot
Proc Natl Acad Sci USA
 , 
1990
, vol. 
87
 (pg. 
3348
-
52
)
27
Black
RA
Rauch
CT
Kozlosky
CJ
, et al.  . 
A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells
Nature
 , 
1997
, vol. 
385
 (pg. 
729
-
33
)
28
Wallis
RS
Paranjape
R
Phillips
M
Identification by two-dimensional gel electrophoresis of a 58-kilodalton tumor necrosis factor-inducing protein of Mycobacterium tuberculosis
Infect Immun
 , 
1993
, vol. 
61
 (pg. 
627
-
32
)
29
Valone
SE
Rich
EA
Wallis
RS
Ellner
JJ
Expression of tumor necrosis factor in vitro by human mononuclear phagocytes stimulated with whole Mycobacterium bovis BCG and mycobacterial antigens
Infect Immun
 , 
1988
, vol. 
56
 (pg. 
3313
-
5
)
30
Barnes
PF
Chatterjee
D
Abrams
JS
, et al.  . 
Cytokine production induced by Mycobacterium tuberculosis lipoarabinomannan: relationship to chemical structure
J Immunol
 , 
1992
, vol. 
149
 (pg. 
541
-
7
)
31
Ribeiro-Rodrigues
R
Resende
CT
Johnson
JL
, et al.  . 
Sputum cytokine levels in patients with pulmonary tuberculosis as early markers of mycobacterial clearance
Clin Diagn Lab Immunol
 , 
2002
, vol. 
9
 (pg. 
818
-
23
)
32
Barnes
PF
Fong
SJ
Brennan
PJ
Twomey
PE
Mazumder
A
Modlin
RL
Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis
J Immunol
 , 
1990
, vol. 
145
 (pg. 
149
-
54
)
33
Bekker
LG
Maartens
G
Steyn
L
Kaplan
G
Selective increase in plasma tumor necrosis factor-α and concomitant clinical deterioration after initiating therapy in patients with severe tuberculosis
J Infect Dis
 , 
1998
, vol. 
178
 (pg. 
580
-
4
)
34
Wallis
RS
Perkins
M
Phillips
M
, et al.  . 
Induction of the antigen 85 complex of M. tuberculosis in sputum: a determinant of outcome in pulmonary tuberculosis
J Infect Dis
 , 
1998
, vol. 
178
 (pg. 
1115
-
21
)
35
Wallis
RS
Phillips
M
Johnson
JL
, et al.  . 
Inhibition of INH-induced expression of M. tuberculosis antigen 85 in sputum: a potential surrogate marker in TB chemotherapy trials
Antimicrob Agents Chemother
 , 
2001
, vol. 
45
 (pg. 
1302
-
4
)
36
Aung
H
Toossi
Z
Wisnieski
JJ
, et al.  . 
Induction of monocyte expression of TNFα by the 30-kD α antigen of M. tuberculosis, and synergism with fibronectin
J Clin Invest
 , 
1996
, vol. 
98
 (pg. 
1261
-
8
)
37
Kindler
V
Sappino
AP
Grau
GE
Piguet
PF
Vassalli
P
The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection
Cell
 , 
1989
, vol. 
56
 (pg. 
731
-
40
)
38
Algood
HM
Lin
PL
Yankura
D
Jones
A
Chan
J
Flynn
JL
TNF influences chemokine expression of macrophages in vitro and that of CD11b+ cells in vivo during Mycobacterium tuberculosis infection
J Immunol
 , 
2004
, vol. 
172
 (pg. 
6846
-
57
)
39
Roach
DR
Bean
AG
Demangel
C
France
MP
Briscoe
H
Britton
WJ
TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection
J Immunol
 , 
2002
, vol. 
168
 (pg. 
4620
-
7
)
40
Hirsch
CS
Ellner
JJ
Russell
DG
Rich
EA
Complement receptor-mediated uptake and tumor necrosis factor-alpha-mediated growth inhibition of Mycobacterium tuberculosis by human alveolar macrophages
J Immunol
 , 
1994
, vol. 
152
 (pg. 
743
-
53
)
41
Flynn
JL
Goldstein
MM
Chan
J
, et al.  . 
Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice
Immunity
 , 
1995
, vol. 
2
 (pg. 
561
-
72
)
42
de Oliveira
MM
da Silva
JC
Amim
LH
, et al.  . 
Single nucleotide polymorphisms (SNPs) of the TNF-α (-238/-308) gene among TB and non TB patients: susceptibility markers of TB occurrence?
Jornal Brasileiro Pneumologia
 , 
2004
, vol. 
30
 (pg. 
461
-
7
)
43
Wallis
RS
Kyambadde
P
Johnson
JL
, et al.  . 
A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis
AIDS
 , 
2004
, vol. 
18
 (pg. 
257
-
64
)
44
Andrieu
JM
Lu
W
Levy
R
Sustained increases in CD4 cell counts in asymptomatic human immunodeficiency virus type 1-seropositive patients treated with prednisolone for 1 year
J Infect Dis
 , 
1995
, vol. 
171
 (pg. 
523
-
30
)
45
Wallis
RS
Kalayjian
R
Jacobson
JM
, et al.  . 
Brief report: a study of the immunology, virology, and safety of prednisone in HIV-1-infected subjects with CD4 cell counts of 200 to 700 mm3
J Acquir Immune Defic Syndr
 , 
2003
, vol. 
32
 (pg. 
281
-
6
)
46
Mayanja-Kizza
H
Jones-Lopez
EC
Okwera
A
, et al.  . 
Immunoadjuvant therapy for HIV-associated tuberculosis with prednisolone: a phase II clinical trial in Uganda
J Infect Dis
 , 
2005
, vol. 
191
 (pg. 
856
-
65
)
47
East African-British Medical Research Councils
Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis: third report
Lancet
 , 
1974
, vol. 
2
 (pg. 
237
-
40
)
48
Bilaceroglu
S
Perim
K
Buyuksirin
M
Celikten
E
Prednisolone: a beneficial and safe adjunct to antituberculosis treatment? A randomized controlled trial
Int J Tuberc Lung Dis
 , 
1999
, vol. 
3
 (pg. 
47
-
54
)
49
Horne
NW
Prednisolone in treatment of pulmonary tuberculosis: a controlled trial. Final report to the Research Committee of the Tuberculosis Society of Scotland
Br Med J
 , 
1960
, vol. 
5215
 (pg. 
1751
-
6
)
50
Tripathy
SP
Ramakrishnan
CV
Nazareth
O
, et al.  . 
Study of chemotherapy regimens of 5 and 7 months' duration and the role of corticosteroids in the treatment of sputum-positive patients with pulmonary tuberculosis in South India
Tubercle
 , 
1983
, vol. 
64
 (pg. 
73
-
91
)
51
Stuck
AE
Minder
CE
Frey
FJ
Risk of infectious complications in patients taking glucocorticosteroids
Rev Infect Dis
 , 
1989
, vol. 
11
 (pg. 
954
-
63
)
52
Wallis
RS
Broder
MS
Wong
JY
Beenhouwer
DO
Granulomatous infections due to tumor necrosis factor blockade: correction
Clin Infect Dis
 , 
2004
, vol. 
39
 (pg. 
1254
-
6
)
53
Dhillon
J
Mitchison
DA
Influence of BCG-induced immunity on the bactericidal activity of isoniazid and rifampicin in experimental tuberculosis of the mouse and guinea-pig
Br J Exp Pathol
 , 
1989
, vol. 
70
 (pg. 
103
-
10
)
54
Batten
JC
McCune
RM
Jr
The influence of corticotrophin and cortisone with antituberculous drugs on population of Mycobacterium tuberculosis in tissues of mice
Br J Exp Pathol
 , 
1957
, vol. 
38
 (pg. 
424
-
37
)
55
Flynn
JL
Chan
J
Rom
WN
Garay
SM
Cole
ST
Eisenach
KD
McMurray
ND
Jacobs
WE
Animal models of tuberculosis
Tuberculosis
 , 
2004
Philadelphia
Lippincott Williams & Wilkins
(pg. 
237
-
50
)
56
Randhawa
PS
Lymphocyte subsets in granulomas of human tuberculosis: an in situ immunofluorescence study using monoclonal antibodies
Pathology
 , 
1990
, vol. 
22
 (pg. 
153
-
5
)
57
Song
XY
Fox
F
Gallo
MA
, et al.  . 
Effects of 2 different anti-tumor necrosis factor-alpha agents in a primate model of subcutaneous abscess formation
J Infect Dis
 , 
2002
, vol. 
185
 (pg. 
204
-
13
)
58
Sonnenberg
P
Murray
J
Glynn
JR
Shearer
S
Kambashi
B
Godfrey-Faussett
P
HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers
Lancet
 , 
2001
, vol. 
358
 (pg. 
1687
-
93
)
59
Weiner
M
Burman
W
Vernon
A
, et al.  . 
Effect of HIV coinfection on two month sputum culture conversion and its associations with TB treatment outcomes [abstract]
Proc Am Thorac Soc
 , 
2005
, vol. 
2
 pg. 
20
 
60
Joloba
ML
Johnson
JL
Namale
A
, et al.  . 
Quantitative sputum bacillary load during rifampin-containing short course chemotherapy in human immunodeficiency virus-infected and non-infected adults with pulmonary tuberculosis
Int J Tuberc Lung Dis
 , 
2000
, vol. 
4
 (pg. 
528
-
36
)
61
el Sadr
WM
Perlman
DC
Matts
JP
, et al.  . 
Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG)
Clin Infect Dis
 , 
1998
, vol. 
26
 (pg. 
1148
-
58
)
62
Narita
M
Ashkin
D
Hollender
ES
Pitchenik
AE
Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS
Am J Respir Crit Care Med
 , 
1998
, vol. 
158
 (pg. 
157
-
61
)
63
Wallis
RS
Broder
MS
Wong
JY
Hanson
JY
Beenhouwer
DO
Granulomatous infectious diseases associated with TNF antagonists
Clin Infect Dis
 , 
2004
, vol. 
38
 (pg. 
1261
-
5
)
64
Centers for Disease Control and Prevention
Reported tuberculosis in the United States, 2000
 , 
2001
Atlanta
US Department of Health and Human Services
 
Available at: http://www.cdc.gov/nchstp/tb/surv/surv2000/default.htm. Accessed 18 May 2005
65
Keane
J
Gershon
S
Wise
RP
, et al.  . 
Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent
N Engl J Med
 , 
2001
, vol. 
345
 (pg. 
1098
-
104
)
66
Lee
JH
Slifman
NR
Gershon
SK
, et al.  . 
Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept
Arthritis Rheum
 , 
2002
, vol. 
46
 (pg. 
2565
-
70
)
67
Bergstrom
L
Yocum
DE
Ampel
NM
, et al.  . 
Increased risk of coccidioidomycosis in patients treated with TNF antagonists
Arthritis Rheum
 , 
2004
, vol. 
50
 (pg. 
1959
-
66
)
68
Serio
RN
Infliximab treatment of sarcoidosis
Ann Pharmacother
 , 
2003
, vol. 
37
 (pg. 
577
-
81
)
69
Lamprecht
P
Voswinkel
J
Lilienthal
T
, et al.  . 
Effectiveness of TNFα blockade with infliximab in refractory Wegener's granulomatosis
Rheumatology (Oxford)
 , 
2002
, vol. 
41
 (pg. 
1303
-
7
)
70
Utz
JP
Limper
AH
Kalra
S
, et al.  . 
Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis
Chest
 , 
2003
, vol. 
124
 (pg. 
177
-
85
)
71
Sandborn
WJ
Hanauer
SB
Katz
S
, et al.  . 
Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial
Gastroenterology
 , 
2001
, vol. 
121
 (pg. 
1088
-
94
)
72
Baert
FJ
D'Haens
GR
Peeters
M
, et al.  . 
Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis
Gastroenterology
 , 
1999
, vol. 
116
 (pg. 
22
-
8
)
73
Di Sabatino
A
Ciccocioppo
R
Cinque
B
, et al.  . 
Defective mucosal T cell death is sustainably reverted by infliximab in a caspase dependent pathway in Crohn's disease
Gut
 , 
2004
, vol. 
53
 (pg. 
70
-
7
)
74
Shen
C
Assche
GV
Colpaert
S
, et al.  . 
Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept
Aliment Pharmacol Ther
 , 
2005
, vol. 
21
 (pg. 
251
-
8
)
75
Van den Brande
JM
Peppelenbosch
MP
van Deventer
SJ
Treating Crohn's disease by inducing T lymphocyte apoptosis
Ann N Y Acad Sci
 , 
2002
, vol. 
973
 (pg. 
166
-
80
)
76
Van den Brande
JM
Braat
H
van den Brink
GR
, et al.  . 
Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease
Gastroenterology
 , 
2003
, vol. 
124
 (pg. 
1774
-
85
)
77
Garcia Vidal
C
Fernandez
SR
Lacasa
JM
Salavert
M
Carballeira
MR
Garau
J
Paradoxical response to anti-tuberculous therapy in infliximab-treated patients with disseminated tuberculosis
Clin Infect Dis
 , 
2005
, vol. 
40
 (pg. 
756
-
9
)

Comments

0 Comments