Home Current Issue Previous Issues Published Ahead-of-Print Collections For Authors Journal Info
Skip Navigation LinksHome > January 9, 2006 - Volume 20 - Issue 2 > Explosion of tuberculin-specific Th1-responses induces immun...
Text sizing:
A
A
A
AIDS:
doi: 10.1097/01.aids.0000202648.18526.bf
Fast Track

Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients

Bourgarit, Annea,b; Carcelain, Guislainea; Martinez, Valeriea; Lascoux, Carolineb; Delcey, Veroniquec; Gicquel, Brigitted; Vicaut, Erice; Lagrange, Philippe Hf; Sereni, Danielb; Autran, Brigittea

Free Access
Article Outline
Collapse Box

Author Information

From the aLaboratory of Cellular Immunology, Pitie-Salpetriere Hospital, Université Pierre et Marie Curie, Paris, France

bDepartment of Internal Medicine, Saint-Louis Hospital, Paris, France

cInternal Medicine department, Lariboisiere Hospital, Paris, France

dMycobacterial genetic unit, Institut Pasteur, Paris, France

eClinical Research Unit, Fernand Widal Hospital, Paris, France

fLaboratory of Microbiology, Saint-Louis Hospital, Paris, France.

Received 18 August, 2005

Revised 19 September, 2005

Accepted 3 October, 2005

Correspondence to B. Autran, Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitie-Salpetriere, Batiment CERVI, 47-83, Boulevard de l'Hopital, 75013 Paris, France. Tel: +33 1 42 17 74 81; fax: +33 1 42 17 74 90; e-mail: brigitte.autran@psl.ap-hop-paris.fr

Collapse Box

Abstract

Objectives: To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes immune restoration syndrome (IRS) in HIV–tuberculosis (TB) coinfected patients.

Design: Prospective, multicenter study of 19 consecutive untreated HIV–TB coinfected patients included when initiating antimycobacterial therapy and sequentially evaluated during HAART and at time of IRS. IRS was defined according to classical clinical diagnostic criteria. Patients were declared IRS− if no IRS occurred within 3 months after HAART initiation.

Methods: Mycobacteria-specific [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-γ quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence.

Results: Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-γ-producing cells increased sharply during IRS (median, 2970 spot forming cells/106 PBMC), but not the cytomegalovirus-specific responses tested as control. Only three IRS+ patients had low ESAT-6− but no 85B-specific responses. IRS− patients did not develop acute PPD-specific responses except in one case. In addition, at time of IRS a peak of PPD-specific Th1 cytokines/chemokines [interleukin (IL)-2, IL-12, IFN-γ, IP10 and monokine-induced by IFN-γ] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation.

Conclusion: An acute exacerbation of Th1 responses against mycobacterial antigens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.

Back to Top | Article Outline

Introduction

First described in HIV-infected patients with Mycobacterium avium complex infection receiving zidovudine monotherapy [1], immune restoration syndrome (IRS) in patients suffering from tuberculosis (TB) became extremely frequent (29–36%) [2] with the HAART era. Classically, IRS occurs in patients co-infected with TB and HIV, naive of HAART, with advanced HIV disease, when both therapies are initiated simultaneously or at a short interval. Usually, clinical symptoms include fever, lymphadenopathy, worsening of respiratory and other initial TB symptoms [2]. Major criteria defining IRS have been proposed [3] whatever the underlying opportunistic event, including an atypical presentation of opportunistic infection (OI) or tumours in patients responding to HAART (decrease in plasma HIV RNA level more than 1 log10 copies/ml), without any alternative explanation (drug resistance, other OI) and with evidence for immune restoration, as minor criteria. However IRS raises three clinically relevant issues: first, diagnosis is difficult as IRS should be distinguished from treatment failure or resistance or other opportunistic diseases; second, IRS treatment in some life-threatening cases is still empirically based on steroids, which are uneasy to introduce in such immunocompromised patients; third, determination of IRS risk factors could help clinicians to determine their therapeutic strategy, i.e., delaying or not HAART introduction [4].

The pathophysiology of IRS is not yet totally elucidated. Acute proinflammatory cytokine [interleukin (IL)-6] production has been demonstrated during IRS [5,6] but its source remains unknown. In addition, a strong and dominant hypothesis is that IRS would be associated with restoration of mycobacteria-specific T-lymphocyte response with either recirculation or proliferation of memory T cells after HAART has reduced the plasma viral load (VL) [7,8]. This hypothesis is only suggested but not yet demonstrated, except for the restoration of delayed-type hypersensitivity (DTH) skin test to purified protein derivative (PPD) [9].

To determine whether IRS is due to an acute restoration of a Th1 TB-specific response that causes its characteristic major inflammatory syndrome we conducted a prospective multicenter study of patients co-infected with HIV and TB. We describe our preliminary results here.

Back to Top | Article Outline

Patients and methods

Patients

Twenty-nine consecutive TB-HIV co-infected untreated patients were prospectively included when beginning anti-TB treatment. Inclusion criteria were: HIV-1 infection, no previous HAART, CD4 cell count below 200 cells/μl, anti-TB therapy initiated within a maximum of 1 week before inclusion and indication to further HAART initiation. Inclusion was secondly confirmed when M. tuberculosis infection was proved (positive culture or histological findings). Patients were evaluated when initiating antimycobacterial therapy (TBK) and HAART (M0) and at 1, 3, 6 and 12 months after HAART initiation (M1,3,6,12). In addition, patients with IRS (IRS+) were evaluated at IRS time (TIRS) and 20 days later. IRS was defined as follows [3]: recurrence of inflammatory reaction [fever, elevated c-reactive protein (CRP)], enlargement of pre-existing lesions, or development of new lesions (lymph nodes, pleuritis) with no mycobacterium resistance, no positive culture specimen, no other diagnosis and with a response to HAART (HIV RNA decrease > 1 log copies/ml). Patients who did not experience IRS within 3 months after HAART initiation were defined as IRS−.

The study was accepted by the Saint-Louis Hospital Institutional Ethical Committee and all patients signed an informed consent.

Back to Top | Article Outline

Methods

ELISPOT assay for quantification of mycobacterum-specific Th1 cells

Antigen-specific Th1 cells producing interferon (IFN)-γ were prospectively quantified on fresh peripheral blood mononuclear cells (PBMC) by ELISpot as described [10], after a 40-h stimulation with mycobacterial extracts (PPD, 1 μg/ml; Statens Serum Institute, Copenhagen, Denmark), ESAT-6 recombinant protein (1 μg/ml, kindly provided by Statens Serum Institute) and 85B (2 μg/ml; Lionex-Diagnostics and Therapeutics GmbH, Braunschweig, Germany). Controls included cytomegalovirus (CMV) extracts (Behring, Liederbach, Germany), HIV-1 p24 (Protein-Sciences, Meriden, USA), phytohaemagglutinin (Murex, Paris, France) and medium alone. Spots were counted using an ELISpot reader (Zeiss, Le Pecq, France) and data were expressed as spot forming cells (SFC)/106 PBMC. Results were considered as positive if above a 50 SFC/106 PBMC after subtraction of the mean background obtained with cells alone.

Back to Top | Article Outline
Cytokine/chemokine production quantification

Fresh PBMC were stimulated for cytokine/chemokine production with the same antigens: PPD and CMV as above. Culture supernatants were collected at day 2 and cryopreserved. Quantification of 25 inflammatory and immunomodulatory cytokines/chemokines [IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40, IL-13, IL-15, IL-17, IFN-γ, tumour necrosis factor (TNF)-α, granulocyte-macrophage colony stimulating factor (GM–CSF), MIP-1α, MIP-1β, MCP-1, monokine-induced by IFN-γ (MIG), RANTES, IP-10, Eotaxin] was performed for four patients (three IRS+, one IRS−) using the multiplexed sandwich immunoassay (Human-25-plex, Biosource, Montrouge, France) based on flowmetric Luminex technology (Luminex-100, Clinisciences, Montrouge, France) as published [11]. The IFN-γ production was quantified on the same supernatants by a Biosource ELISA kit.

Back to Top | Article Outline
Lymphocyte phenotyping

CD4 and CD8 T-lymphocyte phenotype was analysed in fresh whole blood by four-colour flow cytometry using standard methods [7] with the following antibodies: anti-HLA-DR-FITC (Immunotech), anti-CD25-PE (Becton-Dickinson), anti-CD4-PerCPCy5 (Becton-Dickinson) or anti-CD8-PerCP (Becton-Dickinson) and anti-CD3-APC (Becton-Dickinson). Stained cells were analysed on a FACScalibur (Becton-Dickinson) as described.

Back to Top | Article Outline
Statistical analysis

Comparisons between groups were made using non-parametric tests (Fischer exact and Mann–Whitney test) as appropriate.

Back to Top | Article Outline

Results

Twenty-nine consecutive TB–HIV co-infected untreated patients were prospectively included when they began anti-TB treatment. Ten were then excluded for the following reasons: four had unproven tuberculosis, five moved and one was rapidly transferred to the intensice care unit. The other 19 were followed for at least 3 months after initiating HAART. Seven of them (39%) experienced IRS within a median of 23 (range, 12–85) days after M0. IRS clinical manifestations are listed in Table 1. Three patients received oral steroid therapy with rapid recovery; at time of IRS, HAART was transiently stopped for one of them. Patients with (IRS+) and without (IRS−) IRS did not differ in terms of ethnicity, age, sex, dissemination of TB or time between TBK and M0 (27 versus 45 days respectively; non-significant). Median CD4 cell counts at M0 were lower, though not significantly, in IRS+ patients (median 32/μl for IRS+ versus 60/μl for IRS−; P = 0.052) and rose at M3 by 107/μl in IRS+ versus 51/μl in IRS− patients (P = 0.02). The decrease in plasma VL at M1 did not differ between the groups (−5.7 and 5.2 log10 HIV RNA/ml for IRS+ and IRS− respectively).

Table 1
Table 1
Image Tools

The number of PPD-specific cells producing IFN-γ did not differ at baseline (M0) between the groups (44 versus 36 SFC/106 PBMC IRS+/IRS−, non-significant) but their proportion increased sharply during IRS with a median 35-fold amplification and reached a maxima median of 2970 (range, 616–3744) SFC/106 PBMC in the seven IRS+ patients (Fig. 1a and b, left panel). This explosive reactivity did not affect the CMV-specific responses from IRS+ patients. The IRS− patients did not display a similar acute increase in PPD-specific responses (maxima median of 430 SFC/106PBMC, P = 0.002) even in the subgroup (n = 6) with a CD4 gain above 50 cells/mm3 at M3 (P = 0.015). One IRS− patient, however, had an acute increase of 1676 SFC/106PBMC at M3 without clinical IRS nor TB relapse; HAART at this time was no longer effective. Two other IRS− patients had high PPD-specific responses at baseline that were maintained under HAART (Fig. 1a, right). In addition, in IRS− patients CMV and PPD responses were similar, though with a trend toward higher CMV-specific responses than in IRS+ patients ((maxima median) 415 SFC/106PBMC versus 150 SFC/106PBMC, P = 0.20) (Fig. 1a and b).

Fig. 1
Fig. 1
Image Tools
Fig. 1
Fig. 1
Image Tools

When comparing the reactivity against the three mycobacteria antigens tested, we found that only three IRS+ patients had ESAT-6-specific positive responses during IRS with very low frequencies of 58, 142 and 318 SFC/106 PBMC (Fig. 1b). Furthermore, only two IRS− patients, both with CD4 cell counts > 100/μl, recognized both ESAT-6 and PPD during follow-up (data not shown). In contrast, neither IRS+ nor IRS− patients displayed 85B-specific response at baseline and during follow-up.

An extensive proteomic analysis was performed to evaluate the in vitro production of 25 inflammatory and immunomodulatory cytokines/chemokines in antigen-stimulated PBMC supernatants from four patients (three IRS+, one IRS−). Two distinct patterns were observed during IRS. First, PPD-specific IFN-γ production peaked together with other PPD-specific Th-1 related cytokines/chemokines (IL-2, IL-12, IP10 and MIG) (Fig. 1c), but no Th-2 cytokine peak occurred (IL-4, IL-5, IL-13, IL-15). Second, inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, IL-10, RANTES and MCP-1) (Fig. 1d) peaked, produced by both unstimulated and antigen-stimulated cells. In addition, PPD-specific cytokine/chemokine production far exceeded the CMV-specific response in IRS+ patients, while the CMV-reactivity predominated in the IRS− patient (Fig. 1d, right).

Finally, prospective flow cytometry analysis showed increased expression of T-cell activation markers at time of IRS. Indeed, CD4/DR T cells increased from 55% at M0 up to 79% at IRS and 81% at M3, following the same kinetics than the PPD-specific IFN-γ-producing responses (data not shown). As expected, CD4/DR T cells decreased during HAART in IRS− patients, from 55% down to 40% at M3 (P = 0.06, at M3 between IRS+ and IRS− patients).

Back to Top | Article Outline

Discussion

This prospective sequential study of HIV and TB co-infected patients initiating anti-TB and HAART therapies provides the first demonstration that, in this setting, IRS do correspond to an exacerbation of TB-specific Th1 responses with proinflammatory events during the immune reconstitution allowed by HAART.

It is well known that recovery of a PPD-specific response is a characteristic of immune reconstitution with HAART [12–15]. Our prospective study differs from others by clearly showing an exceptionally acute, intense and reproducible kinetic of the PPD-specific response concurrent with the acute inflammatory clinical symptoms described as IRS. This abrupt response was absent in only one IRS + patient who stopped HAART during IRS and received corticosteroids. One IRS− patient showed a similar peak though with no clinical diagnosis of IRS but with poor HAART observance and immunovirological control. This kinetics of acute PPD-specific response was not correlated to the amount of CD4 cell recovery.

Though the hypothesis had been previously formulated, similar findings had not been demonstrated yet, possibly due to the retrospective characteristics of previous studies. In addition, we show the exacerbated mycobacteria-specific response was limited to some persistent antigens contained in PPD but did not affect the mycobacterial proteins ESAT-6 and 85B, suggesting differences in kinetics of persistence or expression levels between antigens involved in IRS. This finding is critical for diagnosis because new tuberculosis-diagnostic tests based on ESAT-6 [16] would have missed this acute response.

The sharp amplification of IFN-γ producing mycobacteria-specific T cells was associated with an acute burst of other Th-1 and proinflammatory cytokines/chemokines, in accordance with Stone et al. [6] showing high serum IL-6 levels during IRS. Both phenomena correlate with the abrupt onset of the clinical findings [2]: lymph node enlargement and functional granuloma formation [17]. We therefore propose that an excessive restoration of PPD-specific Th1 response with no Th2 balance is responsible for enlargement of TB granuloma lesions and is associated with an acute release of non-specific pro-inflammatory cytokines and chemokines inducing the systemic inflammatory syndrome. This latter findings support the use of systemic anti-inflammatory and/or immunosuppressive agents in severe IRS cases. However these results are still preliminary and need to be confirmed on a larger scale.

This mechanism can probably be extended to non-HIV patients experiencing equivalent paradoxical reactions during anti-TB therapy. In some non-HIV patients, IFN-γ secretion, missing during active TB infection, reappears during anti-mycobacterial treatment [18]. This IFN-γ production may be particularly strong concurrently to the restoration of immune response in profoundly immune-suppressed patients. No identified factors explain why such physiologic response to mycobacterial antigens becomes so intense, sometimes life-threatening. However diverse genetic factors affecting the Th1–Th2 balance might determine predisposition to IRS and its severity in various infections as already proposed by P. Price [19].

In conclusion, an acute exacerbation of Th1 responses against some mycobacterial antigens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.

Back to Top | Article Outline

Acknowledgments

This work was supported by Agence Nationale pour la Recherche sur le Sida et les hépatites virales (ANRS). A. Bourgarit is a SIDACTION fellow. We are especially grateful to the PARADOX TB Study group: S. Abgrall, A. Baakili, A-M Béglé, F. Besse, D. Bollens, O. Bouchaud, P. Bursachi, J. Cadranel, J. Camuset, C. Chakvetadze, J. Delgado, M. Diemer, B. Dupont, S. Elmarsafy, O. Fain, L. Fonquernie, A. Furco, P.-M. Girard, C. Grillot-Courvalin, J.F. Grivois, A. Guignet, M.C. Guilleminot, J.-L. Herrmann, V. Jeantils, V. Joly, V. Jouis, P. Klutse, K. Lacombe, M. Lafaurie, R. Lahoulou, A. Lavolé, B. Lefebvre, A. Lefort, E. Letellier, O. Lortholary, A. Metro, M. Trumeau, J.-L. Meynard, M.-C. Meyohas, J.-M. Molina, G. Obenga, M. Parrinello, O. Pelet, C. Pintado, D. Ponscarme, A. Rami, W. Rozenbaum, H. Sahli, P. Sellier, L. Slama, S. Courtial, R. Tubiana, J. Stirnemann, S. Tassi, O. Taulera, H. Touitou, I. Vacher, F. Vincent, P. Yeni. We are also grateful to A. Samri for her monitoring. The authors wish to thank Cliniscience for their lending the Luminex automat.

Special acknowledgement to J.A. Cahn for her editing of the manuscript.

Back to Top | Article Outline

References

1. French MA, Mallal SA, Dawkins RL. Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients. AIDS 1992; 6:1293–1297.

2. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5:361–373.

3. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18:1615–1627.

4. Dean GL, Edwards SG, Ives NJ, Matthews G, Fox EF, Navaratne L, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002; 16:75–83.

5. Morlese JF, Orkin CM, Abbas R, Burton C, Qazi NA, Nelson MR, et al. Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection. AIDS 2003; 17:1411–1413.

6. Stone SF, Price P, Keane NM, Murray RJ, French MA. Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART. HIV Med 2002; 3:21–27.

7. Li TS, Tubiana R, Katlama C, Calvez V, Ait Mohand H, Autran B. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 1998; 351:1682–1686.

8. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277:112–116.

9. 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; 158:157–161.

10. Martinez V, Costagliola D, Bonduelle N, O'go N, Schnuriger A, Theodorou I, et al. Combination of HIV-1-specific CD4 Th1 cell responses and IgG2 antibodies is the best predictor for persistence of long-term nonprogression. J Infect Dis 2005; 191:2053–2063.

11. Carson RT, Vignali DA. Simultaneous quantitation of 15 cytokines using a multiplexed flow cytometric assay. J Immunol Methods 1999; 227:41–52.

12. Havlir DV, Schrier RD, Torriani FJ, Chervenak K, Hwang JY, Boom WH. Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in human immunodeficiency virus-infected subjects. J Infect Dis 2000; 182:1658–1663.

13. Wendland T, Furrer H, Vernazza PL, Frutig K, Christen A, Matter L, et al. HAART in HIV-infected patients: restoration of antigen-specific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia. AIDS 1999; 13:1857–1862.

14. Hengel RL, Allende MC, Dewar RL, Metcalf JA, Mican JM, Lane HC. Increasing CD4+ T cells specific for tuberculosis correlate with improved clinical immunity after highly active antiretroviral therapy. AIDS Res Hum Retroviruses 2002; 18:969–975.

15. Foudraine NA, Hovenkamp E, Notermans DW, Meenhorst PL, Klein MR, Lange JM, et al. Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infected patients. AIDS 1999; 13:177–184.

16. Mori T, Sakatani M, Yamagishi F, Takashima T, Kawabe Y, Nagao K, et al. Specific detection of tuberculosis infection: an interferon-gamma-based assay using new antigens. Am J Respir Crit Care Med 2004; 170:59–64.

17. Lawn SD, Macallan DC. Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person. Clin Infect Dis 2004; 38:154–155.

18. Hirsch CS, Toossi Z, Othieno C, Johnson JL, Schwander SK, Robertson S, et al. Depressed T-cell interferon-gamma responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. J Infect Dis 1999; 180:2069–2073.

19. Price P, Morahan G, Huang D, Stone E, Cheong KY, Castley A, et al. Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases. AIDS 2002; 16:2043–2047.

Cited By:

This article has been cited 59 time(s).

Microbes and Infection
CXCL10/IP-10 release is induced by incubation of whole blood from tuberculosis patients with ESAT-6, CFP10 and TB7.7
Ruhwald, M; Bjerregaard-Andersen, M; Rabna, P; Kofoed, K; Eugen-Olsen, J; Ravn, P
Microbes and Infection, 9(7): 806-812.
10.1016/j.micinf.2007.02.021
CrossRef
Hiv Medicine
Immunological profiles of immune restoration disease presenting as mycobacterial lymphadenitis and cryptococcal meningitis
Tan, D; Yong, Y; Tan, H; Kamarulzaman, A; Tan, L; Lim, A; James, I; French, M; Price, P
Hiv Medicine, 9(5): 307-316.
10.1111/j.1468-1293.2008.00565.x
CrossRef
Cytokine
Cytokine profiles of HIV patients with pulmonary tuberculosis resulting from adjunct immunotherapy with herbal phytoconcentrates Dzherelo and Anemin
Nikolaeva, LG; Maystat, TV; Pylypchuk, VS; Volyanskii, YL; Frolov, VM; Kutsyna, GA
Cytokine, 44(3): 392-396.
10.1016/j.cyto.2008.10.009
CrossRef
Journal of Infection
Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection
De Lavaissiere, M; Manceron, V; Bouree, P; Garcon, L; Bisaro, F; Delfraissy, JF; Lambotte, O; Goujard, C
Journal of Infection, 58(3): 245-247.
10.1016/j.jinf.2008.11.010
CrossRef
Journal of Inflammation-London
Does CD4+CD25+foxp3+cell (Treg) and IL-10 profile determine susceptibility to immune reconstitution inflammatory syndrome (IRIS) in HIV disease?
Shankar, EM; Vignesh, R; Velu, V; Murugavel, KG; Sekar, R; Balakrishnan, P; Lloyd, CAC; Saravanan, S; Solomon, S; Kumarasamy, N
Journal of Inflammation-London, 5(): -.
ARTN 2
CrossRef
Parasite Immunology
Immune reconstitution disease associated with parasitic infections following antiretroviral treatment
Lawn, SD; Wilkinson, RJ
Parasite Immunology, 28(): 625-633.
10.1111/j.1365-3024.2006.00900.x
CrossRef
Clinical Infectious Diseases
Therapeutic Use of Infliximab in Tuberculosis to Control Severe Paradoxical Reaction of the Brain and Lymph Nodes
Blackmore, TK; Manning, L; Taylor, WJ; Wallis, RS
Clinical Infectious Diseases, 47(): E83-E85.
10.1086/592695
CrossRef
European Journal of Immunology
Proliferation of weakly suppressive regulatory CD4(+) T cells is associated with over-active CD4(+) T-cell responses in HIV-positive patients with mycobacterial immune restoration disease
Seddiki, N; Sasson, SC; Santner-Nanan, B; Munier, M; van Bockel, D; Ip, S; Marriott, D; Pett, S; Nanan, R; Cooper, DA; Zaunders, JJ; Kelleher, AD
European Journal of Immunology, 39(2): 391-403.
10.1002/eji.200838630
CrossRef
Vaccine
Influence of antigen exposure on the loss of long-term memory to childhood vaccines in HIV-infected patients
Puissant-Lubrano, B; Combadiere, B; Duffy, D; Wincker, N; Frachette, MJ; Ait-Mohand, H; Verrier, B; Katlama, C; Autran, B
Vaccine, 27(): 3576-3583.
10.1016/j.vaccine.2009.03.050
CrossRef
Oral Diseases
Immune reconstitution inflammatory syndrome after highly active antiretroviral therapy: a review
Tsang, CSP; Samaranayake, LP
Oral Diseases, 16(3): 248-256.
10.1111/j.1601-0825.2009.01628.x
CrossRef
Plos One
Improving T-Cell Assays for the Diagnosis of Latent TB Infection: Potential of a Diagnostic Test Based on IP-10
Ruhwald, M; Petersen, J; Kofoed, K; Nakaoka, H; Cuevas, LE; Lawson, L; Squire, SB; Eugen-Olsen, J; Ravn, P
Plos One, 3(8): -.
ARTN e2858
CrossRef
International Journal of Tuberculosis and Lung Disease
Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis
Burman, W; Weis, S; Vernon, A; Khan, A; Benator, D; Jones, B; Silva, C; King, B; LaHart, C; Mangura, B; Weiner, M; El-Sadr, W
International Journal of Tuberculosis and Lung Disease, 11(): 1282-1289.

Southern African Journal of Hiv Medicine
Hiv/Tb: When Is It Safe to Start Haart?
Wood, R
Southern African Journal of Hiv Medicine, (): 18-+.

Clinical Microbiology Reviews
Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms
Price, P; Murdoch, DM; Agarwal, U; Lewin, SR; Elliott, JH; French, MA
Clinical Microbiology Reviews, 22(4): 651-+.
10.1128/CMR.00015-09
CrossRef
AIDS Research and Human Retroviruses
Immunologic Markers as Predictors of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in HIV and Tuberculosis Coinfected Persons in Thailand
Van Tieu, H; Ananworanich, J; Avihingsanon, A; Apateerapong, W; Sirivichayakul, S; Siangphoe, U; Klongugkara, S; Boonchokchai, B; Hammer, SM; Manosuthi, W
AIDS Research and Human Retroviruses, 25(): 1083-1089.
10.1089/aid.2009.0055
CrossRef
Bmc Infectious Diseases
T-cell and serological responses to Erp, an exported Mycobacterium tuberculosis protein, in tuberculosis patients and healthy individuals
Martinez, V; Carcelain, G; Badell, E; Jouan, M; Mauger, I; Sellier, P; Truffot, C; Bricaire, F; Arend, SM; Ottenhoff, T; Autran, B; Gicquel, B
Bmc Infectious Diseases, 7(): -.
ARTN 83
CrossRef
American Journal of Respiratory and Critical Care Medicine
Type 1 Helper T Cells and FoxP3-positive T Cells in HIV-Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome
Meintjes, G; Wilkinson, KA; Rangaka, MX; Skolimowska, K; Van Veen, K; Abrahams, M; Seldon, R; Pepper, DJ; Rebe, K; Mouton, P; Van Cutsem, G; Nicol, MP; Maartens, G; Wilkinson, RJ
American Journal of Respiratory and Critical Care Medicine, 178(): 1083-1089.
10.1164/rccm.200806-858OC
CrossRef
Revue De Medecine Interne
Immune reconstitution inflammatory syndrome (IRIS syndrome)
Sereni, D; Bourgarit, A
Revue De Medecine Interne, 30(): S15-S16.
10.1016/j.revmed.2009.03.002
CrossRef
Drug Discovery Today
Combined therapy for tuberclosis and HIV-1: the challenge for drug discovery
Pepper, DJ; Meintjes, GA; Mcllleron, H; Wilkinson, RJ
Drug Discovery Today, 12(): 980-989.
10.1016/j.drudis.2007.08.001
CrossRef
Revista Chilena De Infectologia
Tuberculosis in HIV positive individuals
Balcells, ME
Revista Chilena De Infectologia, 26(2): 126-134.

Clinical Infectious Diseases
Novel Relationship between Tuberculosis Immune Reconstitution Inflammatory Syndrome and Antitubercular Drug Resistance
Meintjes, G; Rangaka, MX; Maartens, G; Rebe, K; Morroni, C; Pepper, DJ; Wilkinson, KA; Wilkinson, RJ
Clinical Infectious Diseases, 48(5): 667-676.
10.1086/596764
CrossRef
Clinical Immunology
D-Dimer and CRP levels are elevated prior to antiretroviral treatment in patients who develop IRIS
Porter, BO; Ouedraogo, GL; Hodge, JN; Smith, MA; Pau, A; Roby, G; Kwan, R; Bishop, RJ; Rehm, C; Mican, J; Sereti, I
Clinical Immunology, 136(1): 42-50.
10.1016/j.clim.2010.02.010
CrossRef
Clinical and Experimental Immunology
Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot technology in human immunodeficiency virus (HIV)-1 patients with advanced disease
Clark, SA; Martin, SL; Pozniak, A; Steel, A; Ward, B; Dunning, J; Henderson, DC; Nelson, M; Gazzard, B; Kelleher, P
Clinical and Experimental Immunology, 150(2): 238-244.
10.1111/j.1365-2249.2007.03477.x
CrossRef
Respirology
Pulmonary complications of immune reconstitution inflammatory syndromes in HIV-infected patients
Crothers, K; Huang, L
Respirology, 14(4): 486-494.
10.1111/j.1440-1843.2008.01468.x
CrossRef
Clinical Infectious Diseases
Assessing the Contribution of the Immune Reconstitution Inflammatory Syndrome to Mortality in Developing Country Antiretroviral Therapy Programs
Davies, MA; Meintjes, G
Clinical Infectious Diseases, 49(6): 973-975.
10.1086/605501
CrossRef
Journal of Infectious Diseases
Immunopathogenesis and Diagnosis of Tuberculosis and Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome during Early Antiretroviral Therapy
Elliott, JH; Vohith, K; Saramony, S; Savuth, C; Dara, C; Sarim, C; Huffam, S; Oelrichs, R; Sophea, P; Saphonn, V; Kaldor, J; Cooper, DA; Vun, MC; French, MA
Journal of Infectious Diseases, 200(): 1736-1745.
10.1086/644784
CrossRef
Clinical Infectious Diseases
HIV-Associated Tuberculosis: Clinical Update
Swaminathan, S; Padmapriyadarsini, C; Narendran, G
Clinical Infectious Diseases, 50(): 1377-1386.
10.1086/652147
CrossRef
Journal of Immunology
Tuberculosis-Associated Immune Restoration Syndrome in HIV-1-Infected Patients Involves Tuberculin-Specific CD4 Th1 Cells and KIR-Negative gamma delta T Cells
Bourgarit, A; Carcelain, G; Samri, A; Parizot, C; Lafaurie, M; Abgrall, S; Delcey, V; Vicaut, E; Sereni, D; Autran, B
Journal of Immunology, 183(6): 3915-3923.
10.4049/jimmunol.0804020
CrossRef
Sexually Transmitted Infections
Montelukast in the treatment of HIV associated immune reconstitution disease
Hardwick, C; White, D; Morris, E; Monteiro, EF; Breen, RA; Lipman, M
Sexually Transmitted Infections, 82(6): 513-514.
10.1136/sti.2005.017863
CrossRef
Journal of Virology
Diminished production of monocyte proinflammatory cytokines during human immunodeficiency virus viremia is mediated by type I interferons
Tilton, JC; Johnson, AJ; Luskin, MR; Manion, MM; Yang, J; Adelsberger, JW; Lempicki, RA; Hallahan, CW; McLaughlin, M; Mican, JM; Metcalf, JA; Iyasere, C; Connors, M
Journal of Virology, 80(): 11486-11497.
10.1128/JVI.00324-06
CrossRef
American Journal of Respiratory and Critical Care Medicine
Immune reconstitution and "Unmasking" of tuberculosis during antiretroviral therapy
Lawn, SD; Wilkinson, RJ; Lipman, MCI; Wood, R
American Journal of Respiratory and Critical Care Medicine, 177(7): 680-685.
10.1164/rccm.200709-1311PP
CrossRef
Journal of Infectious Diseases
Combination of Host Susceptibility and Virulence of Mycobacterium tuberculosis Determines Dual Role of Nitric Oxide in the Protection and Control of Inflammation
Beisiegel, M; Kursar, M; Koch, M; Loddenkemper, C; Kuhlmann, S; Zedler, U; Staber, M; Hurwitz, R; Kaufmann, SHE
Journal of Infectious Diseases, 199(8): 1222-1232.
10.1086/597421
CrossRef
Lancet Infectious Diseases
Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis
Muller, M; Wandel, S; Colebunders, R; Attia, S; Furrer, H; Egger, M
Lancet Infectious Diseases, 10(4): 251-261.

AIDS Patient Care and Stds
Immune reconstitution syndrome in a patient with AIDS with paradoxically deteriorating brain tuberculoma
Lee, CH; Lui, CC; Liu, JW
AIDS Patient Care and Stds, 21(4): 234-239.
10.1089/apc.2006.0085
CrossRef
Tuberculosis
Anti-PGL-Tb1 responses as an indicator of the immune restoration syndrome in HIV-TB patients
Simonney, N; Dewulf, G; Herrmann, JL; Gutierrez, MC; Vicaut, E; Boutron, C; Leportier, M; Lafaurie, M; Abgrall, S; Sereni, D; Autran, B; Carcelain, G; Bourgarit, A; Lagrange, PH
Tuberculosis, 88(5): 453-461.
10.1016/j.tube.2008.01.006
CrossRef
Clinical Infectious Diseases
Recognition, Diagnosis, and Treatment of Histoplasmosis Complicating Tumor Necrosis Factor Blocker Therapy
Hage, CA; Bowyer, S; Tarvin, SE; Helper, D; Kleiman, MB; Wheat, LJ
Clinical Infectious Diseases, 50(1): 85-92.
10.1086/648724
CrossRef
International Journal of Infectious Diseases
Immune reconstitution inflammatory syndrome associated with Mycobacterium tuberculosis infection: a systematic review
Leone, S; Nicastri, E; Giglio, S; Narciso, P; Ippolito, G; Acone, N
International Journal of Infectious Diseases, 14(4): E283-E291.
10.1016/j.ijid.2009.05.016
CrossRef
Journal of Infectious Diseases
Unmasked Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Disease: A Disease Spectrum after Initiation of Antiretroviral Therapy
Manabe, YC; Breen, R; Perti, T; Girardi, E; Sterling, TR
Journal of Infectious Diseases, 199(3): 437-444.
10.1086/595985
CrossRef
Revista Romana De Medicina De Laborator
Utility of QuantiFeron -TB (R) Gold test in diagnosis of tuberculosis in HIV-infected patients
Dinu, M; Iosipenco, M; Craciun, C; Baicus, C; Draghicenoiu, RN; Gavrila, L
Revista Romana De Medicina De Laborator, 17(4): 31-36.

M S-Medecine Sciences
Immune reconstitution inflammatory syndrome or IRIS
Breton, G
M S-Medecine Sciences, 26(3): 281-289.

Presse Medicale
Paradoxical reactions in tuberculosis
Martinez, V; Bricaire, F
Presse Medicale, 35(): 1747-1750.

Medecine Et Maladies Infectieuses
Impact of a new family on therapeutic strategies: clinician point of view
Poizot-Martin, I
Medecine Et Maladies Infectieuses, 39(): 10-12.

Lancet Infectious Diseases
The immunopathogenesis of mycobacterial immune restoration disease
French, MA
Lancet Infectious Diseases, 6(8): 461-462.

Archives of Internal Medicine
Cytokine profile in fatal human immunodeficiency virus-tuberculosis Epstein-Barr virus-associated Hemophagocytic syndrome
Wong, CK; Wong, BCK; Chan, KCA; Joynt, GM; Yap, FYHY; Lam, CWK; Lee, N; Lee, SS; Cockram, CS; Sung, JJY; Chan, PKS; Lo, YMD; Tang, JW
Archives of Internal Medicine, 167(): 1901-1903.

Biomarkers in Medicine
Biomarkers of HIV immune reconstitution inflammatory syndrome
Bonham, S; Meya, DB; Bohjanen, PR; Boulware, DR
Biomarkers in Medicine, 2(4): 349-361.
10.2217/17520363.2.4.349
CrossRef
Clinical Infectious Diseases
Immune Reconstitution Inflammatory Syndrome: A Reappraisal
French, MA
Clinical Infectious Diseases, 48(1): 101-107.
10.1086/595006
CrossRef
Journal of Infectious Diseases
Immunopathogenesis of Hepatic Flare in HIV/Hepatitis B Virus (HBV)-Coinfected Individuals after the Initiation of HBV-Active Antiretroviral Therapy
Crane, M; Oliver, B; Matthews, G; Avihingsanon, A; Ubolyam, S; Markovska, V; Chang, JJ; Dore, GJ; Price, P; Visvanathan, K; French, M; Ruxrungtham, K; Lewin, SR
Journal of Infectious Diseases, 199(7): 974-981.
10.1086/597276
CrossRef
Clinical Immunology
Deficient in vitro anti-mycobacterial immunity despite successful long-term highly active antiretroviral therapy in HIV-infected patients with past history of tuberculosis infection or disease
Mendonca, M; Tanji, MM; Silva, LCR; Silveira, GG; Oliveira, SC; Duarte, AJS; Benard, G
Clinical Immunology, 125(1): 60-66.
10.1016/j.clim.2007.06.002
CrossRef
Lancet Infectious Diseases
Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings
Meintjes, G; Lawn, SD; Scono, F; Moartens, G; French, MA; Worodria, W; Elliott, JH; Murdoch, D; Wilkinson, RJ; Seyler, C; John, L; van der Loeff, MS; Reiss, P; Lynen, L; Janoff, EN; Gilks, C; Colebunders, R
Lancet Infectious Diseases, 8(8): 516-523.

International Journal of Std & AIDS
Immune reconstitution inflammatory syndrome
Elston, JWT; Thaker, H
International Journal of Std & AIDS, 20(4): 221-224.
10.1258/ijsa.2008.008449
CrossRef
Plos One
Temporal Dynamics of Interferon Gamma Responses in Children Evaluated for Tuberculosis
Herrmann, JL; Belloy, M; Porcher, R; Simonney, N; Aboutaam, R; Lebourgeois, M; Gaudelus, J; De LosAngeles, L; Chadelat, K; Scheinmann, P; Beydon, N; Fauroux, B; Bingen, M; Terki, M; Barraud, D; Cruaud, P; Offredo, C; Ferroni, A; Berche, P; Moissenet, D; Vuthien, H; Doit, C; Bingen, E; Lagrange, PH
Plos One, 4(1): -.
ARTN e4130
CrossRef
International Journal of Infectious Diseases
Correlates for disease progression and prognosis during concurrent HIV/TB infection
Siawaya, JFD; Ruhwald, M; Eugen-Olsen, J; Walzl, G
International Journal of Infectious Diseases, 11(4): 289-299.
10.1016/j.ijid.2007.02.001
CrossRef
Lancet
Tuberculosis
Maartens, G; Wilkinson, RJ
Lancet, 370(): 2030-2043.
10.1016/S0140-6736(07)61262-8
CrossRef
AIDS
Fatal unmasking tuberculosis immune reconstitution disease with bronchiolitis obliterans organizing pneumonia: the role of macrophages
Lawn, SD; Wainwright, H; Orrell, C
AIDS, 23(1): 143-145.
10.1097/QAD.0b013e32831d2a98
PDF (565) | CrossRef
AIDS
Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study
Murdoch, DM; Venter, WD; Feldman, C; Van Rie, A
AIDS, 22(5): 601-610.
10.1097/QAD.0b013e3282f4a607
PDF (128) | CrossRef
AIDS
Immune reconstitution syndrome in tuberculosis and HIV-co-infected patients: Th1 explosion or cytokine storm?
Ruhwald, M; Ravn, P
AIDS, 21(7): 882-884.
10.1097/QAD.0b013e3280b079c8
PDF (349) | CrossRef
AIDS
Reactive haemophagocytic syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases and prognosis
Fardet, L; Lambotte, O; Meynard, J; Kamouh, W; Galicier, L; Marzac, C; de Labarthe, A; Cabane, J; Lebbe, C; Coppo, P; Molina, J; Martinez, V
AIDS, 24(9): 1299-1306.
10.1097/QAD.0b013e328339e55b
PDF (213) | CrossRef
Current Opinion in Infectious Diseases
Respiratory infection complicating HIV infection
Davis, JL; Fei, M; Huang, L
Current Opinion in Infectious Diseases, 21(2): 184-190.
10.1097/QCO.0b013e3282f54fff
PDF (114) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Killer Immunoglobulin-Like Receptor Genotype May Distinguish Immunodeficient HIV-Infected Patients Resistant to Immune Restoration Diseases Associated With Herpes Virus Infections
Price, P; Witt, C; Santis, Dd; French, MA
JAIDS Journal of Acquired Immune Deficiency Syndromes, 45(3): 359-361.
10.1097/QAI.0b013e31805b82a1
PDF (173) | CrossRef
Back to Top | Article Outline
Keywords:

Immune restoration syndrome; HIV-1; tuberculosis; HAART; ESAT-6; PPD

© 2006 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.