Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome

Suzaan Marais, Graeme Meintjes, Dominique J Pepper, Lori E Dodd, Charlotte Schutz, Zahiera Ismail, Katalin A Wilkinson, Robert J Wilkinson, Suzaan Marais, Graeme Meintjes, Dominique J Pepper, Lori E Dodd, Charlotte Schutz, Zahiera Ismail, Katalin A Wilkinson, Robert J Wilkinson

Abstract

Background: Tuberculosis immune reconstitution inflammatory syndrome (IRIS) is a common cause of deterioration in human immunodeficiency virus (HIV)-infected patients receiving tuberculosis treatment after starting antiretroviral therapy (ART). Potentially life-threatening neurological involvement occurs frequently and has been suggested as a reason to defer ART.

Methods: We conducted a prospective study of HIV-infected, ART-naive patients with tuberculous meningitis (TBM). At presentation, patients started tuberculosis treatment and prednisone; ART was initiated 2 weeks later. Clinical and laboratory findings were compared between patients who developed TBM-IRIS (TBM-IRIS patients) and those who did not (non-TBM-IRIS patients). A logistic regression model was developed to predict TBM-IRIS.

Results: Forty-seven percent (16/34) of TBM patients developed TBM-IRIS, which manifested with severe features of inflammation. At TBM diagnosis, TBM-IRIS patients had higher cerebrospinal fluid (CSF) neutrophil counts compared with non-TBM-IRIS patients (median, 50 vs 3 cells ×10(6)/L, P = .02). Mycobacterium tuberculosis was cultured from CSF of 15 TBM-IRIS patients (94%) compared with 6 non-TBM-IRIS patients (33%) at time of TBM diagnosis; relative risk of developing TBM-IRIS if CSF was Mycobacterium tuberculosis culture positive = 9.3 (95% confidence interval [CI], 1.4-62.2). The combination of high CSF tumor necrosis factor (TNF)-α and low interferon (IFN)-γ at TBM diagnosis predicted TBM-IRIS (area under the curve = 0.91 [95% CI, .53-.99]).

Conclusions: TBM-IRIS is a frequent, severe complication of ART in HIV-associated TBM and is characterized by high CSF neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation. The combination of CSF IFN-γ and TNF-α concentrations may predict TBM-IRIS and thereby be a means to individualize patients to early or deferred ART.

Figures

Figure 1.
Figure 1.
Flow diagram of patients with features of meningitis (eg, headache, confusion, vomiting, and/or neck stiffness) screened for study inclusion. aPatients defaulted within 3 months of starting antiretroviral therapy (ART). bTime points of lumbar punctures include tuberculous meningitis (TBM) diagnosis, ART initiation, and 2 weeks after starting ART. cCerebrospinal fluid varicella-zoster virus polymerase chain reaction was performed in 1 patient with who had shingles at time of TBM presentation, which was positive. Abbreviations: ART; antiretroviral therapy, IRIS; immune reconstitution inflammatory syndrome; TB; tuberculosis; TBM, tuberculous meningitis.
Figure 2.
Figure 2.
Serial cerebrospinal fluid (CSF) findings in patients who developed tuberculous meningitis immune reconstitution inflammatory syndrome (left), and those who did not (right), including protein concentrations (A), CSF to blood glucose ratios (B), neutrophil counts (C), and lymphocyte counts (D). Significant differences (P < .05) between time points within groups are indicated. Abbreviations: ART; antiretroviral therapy, CSF cerebrospinal fluid; IRIS; immune reconstitution inflammatory syndrome; TBM, tuberculous meningitis.
Figure 3.
Figure 3.
Predictive model for tuberculous meningitis immune reconstitution inflammatory syndrome (TBM-IRIS; patients depicted by gray triangles) and non-TBM-IRIS (patients depicted by black circles). Tumor necrosis factor–α and interferon-γ concentrations (pg/mL) are reported. Darker gray indicates greater probability of TBM-IRIS, while lighter gray indicates greater probability of not developing TBM-IRIS. Probabilities associated with shading are indicated by the legend. The middle line indicates 50% chance of TBM-IRIS, while the upper and lower gray lines indicate probabilities of 90% and 10%, respectively. Observe that when using the median line to classify patients as TBM-IRIS or non-TBM-IRIS, all but 2 TBM-IRIS and 1 non-TBM-IRIS patients are correctly classified. Several points in the lower left were moved marginally to the right so that all subjects are clearly identifiable. Abbreviations: IFN, interferon; TNF, tumor necrosis factor.

References

    1. Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:516–23.
    1. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365:1471–81.
    1. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365:1482–91.
    1. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365:1492–501.
    1. Meintjes G, Rabie H, Wilkinson RJ, Cotton MF. Tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. Clin Chest Med. 2009;30:797–810.
    1. Oliver BG, Elliott JH, Price P, et al. Mediators of innate and adaptive immune responses differentially affect immune restoration disease associated with Mycobacterium tuberculosis in HIV patients beginning antiretroviral therapy. J Infect Dis. 2010;202:1728–37.
    1. Asselman V, Thienemann F, Pepper DJ, et al. Central nervous system disorders after starting antiretroviral therapy in South Africa. AIDS. 2010;24:2871–6.
    1. Pepper DJ, Marais S, Maartens G, et al. Neurologic manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome: a case series. Clin Infect Dis. 2009;48:e96–107.
    1. Torok ME, Kambugu A, Wright E. Immune reconstitution disease of the central nervous system. Curr Opin HIV AIDS. 2008;3:438–45.
    1. Dautremer J, Pacanowski J, Girard PM, Lalande V, Sivignon F, Meynard JL. A new presentation of immune reconstitution inflammatory syndrome followed by a severe paradoxical reaction in an HIV-1-infected patient with tuberculous meningitis. AIDS. 2007;21:381–2.
    1. Tuon FF, Mulatti GC, Pinto WP, de Siqueira Franca FO, Gryschek RC. Immune reconstitution inflammatory syndrome associated with disseminated mycobacterial infection in patients with AIDS. AIDS Patient Care STDS. 2007;21:527–32.
    1. Lee CH, Lui CC, Liu JW. Immune reconstitution syndrome in a patient with AIDS with paradoxically deteriorating brain tuberculoma. AIDS Patient Care STDS. 2007;21:234–9.
    1. Crump JA, Tyrer MJ, Lloyd-Owen SJ, Han LY, Lipman MC, Johnson MA. Miliary tuberculosis with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy. Clin Infect Dis. 1998;26:1008–9.
    1. Manosuthi W, Kiertiburanakul S, Phoorisri T, Sungkanuparph S. Immune reconstitution inflammatory syndrome of tuberculosis among HIV-infected patients receiving antituberculous and antiretroviral therapy. J Infect. 2006;53:357–63.
    1. Vidal JE, Cimerman S, Schiavon Nogueira R, et al. Paradoxical reaction during treatment of tuberculous brain abscess in a patient with AIDS. Rev Inst Med Trop Sao Paulo. 2003;45:177–8.
    1. Marais S, Scholtz P, Pepper DJ, Meintjes G, Wilkinson RJ, Candy S. Neuroradiological features of the tuberculosis-associated immune reconstitution inflammatory syndrome. Int J Tuberc Lung Dis. 2010;14:188–96.
    1. Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculous meningitis. Clin Infect Dis. 2011;52:1374–83.
    1. Torok ME, Farrar JJ. When to start antiretroviral therapy in HIV-associated tuberculosis. N Engl J Med. 2011;365:1538–40.
    1. Médecins Sans Frontières, Western Cape Province Department of Health, City of Cape Town Department of Health, and University of Cape Town Infectious Disease Epidemiology Unit. Comprehensive TB/HIV services at primary health care level, Khayelitsha annual activity report: 2007–2008. Available at: . Accessed 28 October 2012.
    1. Bhigjee AI, Padayachee R, Paruk H, Hallwirth-Pillay KD, Marais S, Connoly C. Diagnosis of tuberculous meningitis: clinical and laboratory parameters. Int J Infect Dis. 2007;11:348–54.
    1. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004;351:1741–51.
    1. Gibbon CJ, Blockman M, editors. South African medicines formulary. 8th ed. Cape Town, South Africa: Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town; 2008. Antimycobacterials; pp. 301–2.
    1. Tadokera R, Meintjes G, Skolimowska KH, et al. Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome. Eur Respir J. 2011;37:1248–59.
    1. Meintjes G, Skolimowska KH, Wilkinson KA, et al. Corticosteroid-modulated immune activation in the tuberculosis immune reconstitution inflammatory syndrome. Am J Respir Crit Care Med. 2012;186:369–77.
    1. Simon RM, Korn EL, McShane LM, Radmacher MD, Wright GW, Zhao Y. Class prediction. In: Dietz K, Samet J, Gail M, et al., editors. Design and analysis of DNA microarray investigations. 1st ed. New York: Springer; 2004. pp. 108–14.
    1. Sacktor NC, Wong M, Nakasujja N, et al. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS. 2005;19:1367–74.
    1. Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10:251–61.
    1. Burman W, Weis S, Vernon A, et al. Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis. Int J Tuberc Lung Dis. 2007;11:1282–9.
    1. McGee S, Hirschmann J. Use of corticosteroids in treating infectious diseases. Arch Intern Med. 2008;168:1034–46.
    1. Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010;24:2381–90.
    1. Torok ME, Chau TT, Mai PP, et al. Clinical and microbiological features of HIV-associated tuberculous meningitis in Vietnamese adults. PLoS One. 2008;3:e1772.
    1. Bourgarit A, Carcelain G, Martinez V, et al. Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS. 2006;20:F1–7.
    1. Meintjes G, Wilkinson KA, Rangaka MX, et al. Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis-associated immune reconstitution inflammatory syndrome. Am J Respir Crit Care Med. 2008;178:1083–9.
    1. Lawn SD, Wainwright H, Orrell C. Fatal unmasking tuberculosis immune reconstitution disease with bronchiolitis obliterans organizing pneumonia: the role of macrophages. AIDS. 2009;23:143–5.
    1. Barber DL, Mayer-Barber KD, Antonelli LR, et al. Th1-driven immune reconstitution disease in Mycobacterium avium-infected mice. Blood. 2010;116:3485–93.
    1. Simmons CP, Thwaites GE, Quyen NT, et al. Pretreatment intracerebral and peripheral blood immune responses in Vietnamese adults with tuberculous meningitis: diagnostic value and relationship to disease severity and outcome. J Immunol. 2006;176:2007–14.
    1. Patel VB, Bhigjee AI, Bill PL, Connolly CA. Cytokine profiles in HIV seropositive patients with tuberculous meningitis. J Neurol Neurosurg Psychiatry. 2002;73:598–9.
    1. Breton G, Duval X, Estellat C, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis. 2004;39:1709–12.
    1. Michailidis C, Pozniak AL, Mandalia S, Basnayake S, Nelson MR, Gazzard BG. Clinical characteristics of IRIS syndrome in patients with HIV and tuberculosis. Antivir Ther. 2005;10:417–22.
    1. Lawn SD, Meintjes G. Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy. Expert Rev Anti Infect Ther. 2011;9:415–30.
    1. Marais S, Pepper DJ, Schutz C, Wilkinson RJ, Meintjes G. Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting. PLoS One. 2011;6:e20077.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe