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

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.

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.

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.

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.