Dominique J. Pepper

Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome

Objective:Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events. Design:A randomized, double-blind, placebo-controlled trial of prednisone (1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded. Methods:The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day. Results:One hundred and ten participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm {median hospital days 3 [interquartile range (IQR) 0–9] and 0 (IQR 0–3), respectively; P = 0.04}. There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone vs. the placebo arm at 2 and 4 weeks, but not at later time points. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (P = 0.002) and 4 (P = 0.02). Infections on study medication occurred in more participants in prednisone than in placebo arm (27 vs. 17, respectively; P = 0.05), but there was no difference in severe infections (2 vs. 4, respectively; P = 0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrolment. Conclusion:Prednisone reduced the need for hospitalization and therapeutic procedures and hastened improvements in symptoms, performance, and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.

Neurologic Manifestations of Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome: A Case Series

BACKGROUND Paradoxical neurologic tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a potentially life-threatening condition that occurs within 3 months after starting combination antiretroviral therapy (ART). The reports in the published literature are anecdotal, and the prevalence and outcomes of neurologic TB-IRIS are unknown. METHODS We prospectively assessed patients with suspected TB-IRIS from June 2005 through October 2007 at our hospital in Cape Town, South Africa. We defined paradoxical TB-IRIS and paradoxical neurologic TB-IRIS with use of consensus clinical case definitions. We collected data on tuberculosis diagnosis, ART, details of TB-IRIS diagnosis, other opportunistic infections, corticosteroid use, and outcome. RESULTS We reviewed 279 patients with suspected TB-IRIS, 54 (19%) of whom had suspected neurologic TB-IRIS, and 225 (81%) of whom had suspected non-neurologic TB-IRIS. Paradoxical TB-IRIS was diagnosed in 190 patients; 23 (12%) of these 190 patients had neurologic TB-IRIS (95% confidence interval, 7%-17%). Eight had meningitis, 7 had tuberculoma, 5 had both tuberculoma and meningitis, and 3 had radiculomyelopathy. Twenty (87%) of the 23 patients with neurologic TB-IRIS required hospital admission (median duration, 12 days; interquartile range, 6-24 days), and 21 (91%) received corticosteroids (median duration, 58 days; interquartile range, 29-86 days). Outcomes 6 months after the initial assessment for neurologic deterioration were as follows: 16 (70%) of the patients were alive (10 of these patients had documented full physical and mental recovery), 3 (13%) were dead, and 4 (17%) were lost to follow-up. CONCLUSIONS Paradoxical neurologic TB-IRIS accounts for 12% of paradoxical TB-IRIS cases. Neurologic TB-IRIS causes considerable short-term morbidity but has reasonable long-term outcomes. Further research is needed to devise optimal diagnostic and management strategies for patients with tuberculosis who experience neurologic deterioration after starting ART.

Type 1 Helper T Cells and FoxP3-positive T Cells in HIV–Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome

RATIONALE Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) induced by combination antiretroviral therapy (cART) has been attributed to dysregulated expansion of tuberculin PPD-specific IFN-gamma-secreting CD4(+) T cells. OBJECTIVES To investigate the role of type 1 helper T cell expansions and regulatory T cells in HIV-TB IRIS. METHODS Longitudinal and cross-sectional studies of Mycobacterium tuberculosis-specific IFN-gamma enzyme-linked immunospot responses and flow cytometric analysis of blood cells from a total of 129 adults with HIV-1-associated tuberculosis, 98 of whom were prescribed cART. MEASUREMENTS AND MAIN RESULTS In cross-sectional analysis the frequency of IFN-gamma-secreting T cells recognizing early secretory antigenic target (ESAT)-6, alpha-crystallins 1 and 2, and PPD of M. tuberculosis was higher in patients with TB-IRIS than in similar patients treated for both HIV-1 and tuberculosis who did not develop IRIS (non-IRIS; P <or= 0.03). The biggest difference was in the recognition of alpha-crystallin molecules: peptide mapping indicated a polyclonal response. Flow cytometric analysis indicated equal proportions of CD4(+) and CD8(+) cells positive for activation markers HLA-DR and CD71 in both patients with TB-IRIS and non-IRIS patients. The percentage of CD4(+) cells positive for FoxP3 (Forkhead box P3) was low in both groups (TB-IRIS, 5.3 +/- 4.5; non-IRIS, 2.46 +/- 2.46; P = 0.13). Eight weeks of longitudinal analysis of patients with tuberculosis who were starting cART showed dynamic changes in antigen-specific IFN-gamma-secreting T cells in both the TB-IRIS and non-IRIS groups: the only significant trend was an increased response to PPD in the TB-IRIS group (P = 0.041). CONCLUSIONS There is an association between helper T-cell type 1 expansions and TB-IRIS, but the occurrence of similar expansions in non-IRIS brings into question whether these are causal. The defect in immune regulation responsible for TB-IRIS remains to be fully elucidated.

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

Tuberculous meningitis (TBM) immune reconstitution inflammatory syndrome is a severe complication of antiretroviral therapy in human immunodeficiency virus–associated TBM. We found that high cerebrospinal fluid neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation characterize, and cytokine concentrations predict, this syndrome.

Novel Relationship between Tuberculosis Immune Reconstitution Inflammatory Syndrome and Antitubercular Drug Resistance

BACKGROUND Tuberculosis (TB) immune reconstitution inflammatory syndrome (IRIS) is emerging as an important early complication of combination antiretroviral therapy in patients with TB in developing countries. The differential diagnosis of TB IRIS includes deterioration caused by other human immunodeficiency virus-related morbidities and drug-resistant TB. METHODS We prospectively evaluated consecutive patients with suspected TB IRIS from February 2005 through July 2006 at a community-based secondary hospital in Cape Town, South Africa, by means of clinical case definitions for TB IRIS. Specimens were sent for TB culture and susceptibility testing, and a rapid test (FASTplaque-Response) was performed to expedite determination of rifampin susceptibility. RESULTS One hundred patients with suspected TB IRIS were evaluated, 26 of whom were being retreated for TB. IRIS symptoms developed a median of 14 days (interquartile range, 7-25 days) after the initiation of combination antiretroviral therapy. In 7 patients, an alternative opportunistic disease was diagnosed. Rifampin-resistant TB was present in 13 patients, 9 of whom received a diagnosis after study entry (7 of 9 had multidrug-resistant TB). Undiagnosed rifampin-resistant TB was thus present in 10.1% of patients (95% confidence interval, 3.9%-16.4%) who presented with TB IRIS, once those with alternative diagnoses and TB with known rifampin resistance were excluded. In the remaining 80 patients, TB IRIS without rifampin resistance was the final diagnosis. CONCLUSIONS TB IRIS that is clinically indistinguishable from TB IRIS that occurs in the context of drug-susceptible disease may occur in patients with undiagnosed multidrug-resistant TB. Antitubercular drug resistance should be excluded in all cases of suspected TB IRIS, and corticosteroids should be used with caution for patients with presumed TB IRIS until the result of drug-susceptibility testing is known.

Corticosteroid-modulated immune activation in the tuberculosis immune reconstitution inflammatory syndrome.

RATIONALE HIV-tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an immunopathological reaction to mycobacterial antigens induced by antiretroviral therapy. Prednisone reduces morbidity in TB-IRIS, but the mechanisms are unclear. OBJECTIVES To determine the effect of prednisone on the inflammatory response in TB-IRIS (antigen-specific effector T cells, cytokines, and chemokines). METHODS Blood was taken from participants in a randomized placebo-controlled trial of prednisone for TB-IRIS, at 0, 2, and 4 weeks. Participants received prednisone at a dosage of 1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks, or placebo at identical dosages. MEASUREMENTS AND MAIN RESULTS Analyses included IFN-γ enzyme-linked immunospot (ELISPOT), reverse transcription-polymerase chain reaction on peripheral blood mononuclear cells after restimulation with heat-killed Mycobacterium tuberculosis, Luminex multiplex cytokine analysis of corresponding tissue culture supernatants, and Luminex multiplex cytokine analysis of serum. Fifty-eight participants with TB-IRIS (31 receiving prednisone, 27 receiving placebo) were included. In serum, significant decreases in IL-6, IL-10, IL-12 p40, tumor necrosis factor-α, IFN-γ, and IFN-γ-induced protein-10 concentrations during prednisone, but not placebo, treatment were observed. No differences in ELISPOT responses comparing prednisone and placebo groups were shown in response to ESAT-6 (early secreted antigen target-6), Acr1, Acr2, 38-kD antigen, or heat-killed H37Rv M. tuberculosis. Purified protein derivative ELISPOT responses increased over 4 weeks in the prednisone group and decreased in the placebo group (P = 0.007). CONCLUSIONS The beneficial effects of prednisone in TB-IRIS appear to be mediated via suppression of predominantly proinflammatory cytokine responses of innate immune origin, not via a reduction of the numbers of antigen-specific T cells in peripheral blood.

Central Nervous System Disorders after Starting Antiretroviral Therapy in South Africa

Objective:To describe the spectrum of central nervous system (CNS) disease during the first year of antiretroviral therapy (ART) and to determine the contribution of neurological immune reconstitution inflammatory syndrome (IRIS). Design:A prospective observational cohort study conducted over a 12-month period at a public sector referral hospital in South Africa. Methods:HIV-seropositive patients who developed new or recurrent neurological or psychiatric symptom(s) or sign(s) within the first year of starting ART were enrolled. We used the number of patients starting ART in the referral area in the preceding year as the denominator to calculate the incidence of referral for neurological deterioration. Patients with delirium and peripheral neuropathy were excluded. Outcome at 6 months was recorded. Results:Seventy-five patients were enrolled. The median nadir CD4+ cell counts was 64 cells/μl. Fifty-nine percent of the patients were receiving antituberculosis treatment. The incidence of referral for CNS deterioration in the first year of ART was 23.3 cases [95% confidence interval (CI), 18.3–29.2] per 1000 patient-years at risk. CNS tuberculosis (n = 27, 36%), cryptococcal meningitis (n = 18, 24%), intracerebral space occupying lesions (other than tuberculoma) (n = 10, 13%) and psychosis (n = 9, 12%) were the most frequent diagnoses. Paradoxical neurological IRIS was diagnosed in 21 patients (28%), related to tuberculosis in 16 and cryptococcosis in five. At 6 months, 23% of the patients had died and 20% were lost to follow-up. Conclusion:Opportunistic infections, notably tuberculosis and cryptococcosis, were the most frequent causes for neurological deterioration after starting ART. Neurological IRIS occurred in over a quarter of patients.

Human Immunodeficiency Virus-Associated Gastrointestinal Disease: Common Endoscopic Biopsy Diagnoses

The gastrointestinal (GI) tract is a major site of disease in HIV infection: almost half of HIV-infected patients present with GI symptoms, and almost all patients develop GI complications. GI symptoms such as anorexia, weight loss, dysphagia, odynophagia, abdominal pain, and diarrhea are frequent and usually nonspecific among these patients. Endoscopy is the diagnostic test of choice for most HIV-associated GI diseases, as endoscopic and histopathologic evaluation can render diagnoses in patients with non-specific symptoms. In the past three decades, studies have elucidated a variety of HIV-associated inflammatory, infectious, and neoplastic GI diseases, often with specific predilection for various sites. HIV-associated esophageal disease, for example, commonly includes candidiasis, cytomegalovirus (CMV) and herpes simplex virus (HSV) infection, Kaposis sarcoma (KS), and idiopathic ulceration. Gastric disease, though less common than esophageal disease, frequently involves CMV, Mycobacterium avium-intracellulare (MAI), and neoplasia (KS, lymphoma). Small bowel biopsies and intestinal aspirates from HIV-infected patients often show HIV enteropathy, MAI, protozoa (Giardia, Isospora, Cryptosporidia, amebae, Microsporidia), and helminths (Strongyloides stercoralis). Colorectal biopsies demonstrate viral (CMV, HSV), bacterial (Clostridia, Salmonella, Shigella, Campylobacter), fungal (cryptococcosis, histoplasmosis), and neoplastic (KS, lymphoma) processes. Herein, we review HIV-associated GI pathology, with emphasis on common endoscopic biopsy diagnoses.

HIV-associated tuberculous meningitis – diagnostic and therapeutic challenges

HIV-associated tuberculous meningitis (TBM) poses significant diagnostic and therapeutic challenges and carries a dismal prognosis. In this review, we present the clinical features and management of HIV-associated TBM, and compare this to disease in HIV-uninfected individuals. Although the clinical presentation, laboratory findings and radiological features of TBM are similar in HIV-infected and HIV-uninfected patients, some important differences exist. HIV-infected patients present more frequently with extra-meningeal tuberculosis and systemic features of HIV infection. In HIV-associated TBM, clinical course and outcome are influenced by profound immunosuppression at presentation, emphasising the need for earlier diagnosis of HIV infection and initiation of antiretroviral treatment.

Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting.

Background Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM. Methods A retrospective review of cerebrospinal fluid findings and clinical records over a six-month period (March 2009–August 2009). Definite, probable and possible TBM were diagnosed according to published case definitions. Results TBM was diagnosed in 120/211 patients (57%) with meningitis. In 106 HIV-infected patients with TBM, six-month all-cause mortality was lower in those who received antiretroviral therapy (ART) during TB treatment; hazard ratio = 0.30 (95% CI = 0.08–0.82). Factors associated with inpatient mortality in HIV-infected patients were 1) low CD4+ count at presentation; adjusted odds ratio (AOR) = 1.4 (95% confidence interval [CI] = 1.03–1.96) per 50 cells/µL drop in CD4+ count and, 2) higher British Medical Research Council TBM disease grade (2 or 3 versus 1); AOR = 4.8 (95% CI = 1.45–15.87). Interpretation Starting ART prior to or during TB treatment may be associated with lower mortality in patients with HIV-associated TBM. Advanced HIV and worse stage of TBM disease predict in-hospital mortality in patients presenting with TBM.