Here, we aimed to determine the clinical spectrum, predictors and outcomes of paradoxical tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in a resource-limited setting.
Methods
In a prospective cohort, we studied 254 patients with tuberculosis and HIV coinfection commencing antiretroviral therapy (ART). We identified patients with TB-IRIS using the International Network for Studies Against HIV-Associated IRIS (INSHI) case definition. Risk factors and clinical outcomes of TB-IRIS were determined and reported.
Results
A total of 53 (21%) patients developed TB-IRIS a median of 2 weeks (IQR 12–22 days) after starting ART. The majority of the patients (70%) with TB-IRIS had extrapulmonary manifestations of TB-IRIS. In a multiple logistic regression model, baseline haemoglobin <100 g/l (OR 2.23 [95% CI 1.08–4.60]; P=0.031) and baseline CD4+ T-cell count <50 cells/ml (OR 4.13 [95% CI 1.80–9.51]; P=0.001) were significant predictors of IRIS. Seven additional patients fulfilled all INSHI criteria of TB-IRIS but had the episode of TB-IRIS later than 3 months after ART start.
Conclusions
TB-IRIS was a frequent reason for clinical deterioration among patients with TB commencing ART but was not a primary contributor to mortality. Patients with advanced CD4 depletion and anaemia were at increased risk of TB-IRIS. Some patients developed late-onset TB-IRIS and/or a recurrent TB-IRIS episode.
References
1.
CorbettE.L., WattC.J., WalkerN.The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med2003; 163: 1009–1021.
2.
ManosuthiW., ChottanapandS., ThongyenS., ChaovavanichA., SungkanuparphS.Survival rate and risk factors of mortality among HIV/tuberculosis-coinfected patients with and without antiretroviral therapy. J Acquir Immune Defic Syndr2006; 43: 42–46.
3.
BlancF.X., SokT., LaureillardD.Significant enhancement in survival with early (2 weeks) vs. late (8 weeks) initiation of highly active antiretroviral treatment (HAART) in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis. XVIII International AIDS Conference. 18–23 July 2010, Vienna, Austria. Abstract THLBB106.
4.
SeddikiN., SassonS.C., Santner-NananB.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. Eur J Immunol2009; 39: 391–403.
5.
OliverB.G., ElliottJ.H., PriceP.Mediators of innate and adaptive immune responses differentially affect immune restoration disease associated with Mycobacterium tuberculosis in HIV patients beginning antiretroviral therapy. J Infect Dis2010; 202: 1728–1737.
6.
KestensL., SeddikiN., BohjanenP.R.Immunopathogenesis of immune reconstitution disease in HIV patients responding to antiretroviral therapy. Curr Opin HIV AIDS2008; 3: 419–424.
7.
AntonelliL.R., MahnkeY., HodgeJ.N.Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome. Blood2010; 116: 3818–3827.
8.
BourgaritA., CarcelainG., MartinezV.Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS2006; 20: F1–F7.
9.
BourgaritA., CarcelainG., SamriA.Tuberculosis-associated immune restoration syndrome in HIV-1-infected patients involves tuberculin-specific CD4 Th1 cells and KIR-negative gammadelta T cells. J Immunol2009; 183: 3915–3923.
10.
MurdochD.M., VenterW.D., FeldmanC., Van RieA.Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS2008; 22: 601–610.
11.
MichailidisC., PozniakA.L., MandaliaS., BasnayakeS., NelsonM.R., GazzardB.G.Clinical characteristics of IRIS syndrome in patients with HIV and tuberculosis. Antivir Ther2005; 10: 417–422.
BurmanW., WeisS., VernonA.Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis. Int J Tuberc Lung Dis2007; 11: 1282–1289.
14.
KarmakarS., SharmaS.K., VashishthaR.Clinical characteristics of tuberculosis-associated immune reconstitution inflammatory syndrome in North Indian population of HIV/AIDS patients receiving HAART. Clin Dev Immunol2011; 2011: 239021.
15.
ShelburneS.A., VisnegarwalaF., DarcourtJ.Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS2005; 19: 399–406.
16.
LeoneS., NicastriE., GiglioS., NarcisoP., IppolitoG., AconeN.Immune reconstitution inflammatory syndrome associated with Mycobacterium tuberculosis infection: a systematic review. Int J Infect Dis2010; 14: e283–e291.
17.
MeintjesG., LawnS.D., ScanoF.Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis2008; 8: 516–523.
18.
WorodriaW., Massinga-LoembeM., MazakpweD.Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy. J Acquir Immune Defic Syndr2011; 58: 32–37.
19.
World Health Organization.Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents. Recommendations for HIV-prevalent and resource-constrained settings. (Accessed 21 August 2011.) Available from http://whqlibdoc.who.int/hq/2007/WHO_HTM_TB_2007.379_eng.pdf.
20.
Republic of Uganda Ministry of Health.National antiretroviral treatment and care guidelines for adults, adolescents, and children. (Updated July 2008. Accessed 31 August 2011.) Available from http://www.who.int/hiv/amds/uganda_moh_treatment_guidelines.pdf.
21.
LawnS.D., MyerL., BekkerL.G., WoodR.Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS2007; 21: 335–341.
22.
ManosuthiW., Van TieuH., MankatithamW.Clinical case definition and manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS2009; 23: 2467–2471.
23.
NaritaM., AshkinD., HollenderE.S., PitchenickA.E.Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med1998; 158: 157–161.
24.
NavasE., Martin-DavilaP., MorenoL.Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med2002; 162: 97–99.
25.
ElliottJ.H., VohithK., SaramonyS.Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy. J Infect Dis2009; 200: 1736–1745.
26.
LawnS.D., BekkerL.G., MillerR.F.Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis2005; 5: 361–373.
27.
Abdool KarimS.S., NaidooK., GroblerA.Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med2010; 362: 697–706.
28.
Abdool KarimS., NaidooK., PadayatchiN.Optimal timing of ART during TB therapy: findings of the SAPiT Trial.18th Conference on Retroviruses and Opportunistic Infections. 27 February–2-March 2011, Boston, MA, USA. Abstract 39LB.
29.
Eshun-WilsonI., HaversF., NachegaJ.B.Evaluation of paradoxical TB-associated IRIS with the use of standardized case definitions for resource-limited settings. J Int Assoc Physicians AIDS Care (Chic)2010; 9: 104–108.
30.
HavlirD., IveP., KendallM.International randomized trial of immediate vs early ART in HIV+ patients treated for TB: ACTG 5221 STRIDE Study.18th Conference on Retroviruses and Opportunistic Infections. 27 February–2-March 2011, Boston, MA, USA. Abstract 38.
31.
ManosuthiW., KiertiburanakulS., PhoorisriT., SungkanuparphS.Immune reconstitution inflammatory syndrome of tuberculosis among HIV-infected patients receiving antituberculous and antiretroviral therapy. J Infect2006; 53: 357–363.
BretonG., DuvalX., EstellatC.Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis2004; 39: 1709–1712.
34.
MeintjesG., WilkinsonR.J., MorroniC.Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS2010; 24: 2381–2390.
35.
PepperD.J., MaraisS., MaartensG.Neurologic manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome: a case series. Clin Infect Dis2009; 48: e96–e107.
36.
MüllerM., WandelS., ColebundersR., AttiaS., FurrerH., EggerM.Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis2010; 10: 251–261.
37.
HuystV., LynenL., BottieauE., ZolfoM., KestensL., ColebundersR.Immune reconstitution inflammatory syndrome in an HIV/TB co-infected patient four years after starting antiretroviral therapy. Acta Clin Belg2007; 62: 126–129.
38.
HaddowL.J., ColebundersR., MeintjesG.Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis2010; 10: 791–802.
