Robert S. Wallis

Granulomatous Infectious Diseases Associated with Tumor Necrosis Factor Antagonists

The relationship between the use of tumor necrosis factor antagonists and onset of granulomatous infection was examined using data collected through the Adverse Event Reporting System of the US Food and Drug Administration for January 1998-September 2002. Granulomatous infections were reported at rates of approximately 239 per 100,000 patients who received infliximab and approximately 74 per 100,000 patients who received etanercept (P<.001). Tuberculosis was the most frequently reported disease, occurring in approximately 144 and approximately 35 per 100,000 infliximab-treated and etanercept-treated patients, respectively (P<.001). Candidiasis, coccidioidomycosis, histoplasmosis, listeriosis, nocardiosis, and infections due to nontuberculous mycobacteria were reported with significantly greater frequency among infliximab-treated patients. Seventy-two percent of these infection occurred < or =90 days after starting infliximab treatment, and 28% occurred after starting etanercept treatment (P<.001). These data indicate a risk of granulomatous infection that was 3.25-fold greater among patients who received infliximab than among those who received etanercept. The clustering of reports shortly after initiation of treatment with infliximab is consistent with reactivation of latent infection.

A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis

Objective: Tumor necrosis factor (TNF), an important inflammatory mediator in tuberculosis, has been implicated in causing accelerated HIV disease progression in HIV-associated tuberculosis. However, TNF blockade, particularly by monoclonal antibody, has been associated with the reactivation of latent Mycobacterium tuberculosis infection by the impairment of mycobacterial immunity. This phase 1 study examined the safety, microbiology, immunology, and virology of TNF blockade using etanercept (soluble TNF receptor, Enbrel) during the initial treatment of HIV-associated tuberculosis. Design: A single-arm trial, with key endpoints compared with historical controls, conducted in Mulago Hospital, Kampala, Uganda. Subjects: Sixteen HIV-1-infected patients and 42 CD4-frequency-matched controls with sputum smear-positive tuberculosis and CD4 cell counts > 200 cells/μl. Intervention: Etanercept 25 mg, eight doses administered subcutaneously twice weekly beginning on day 4 of tuberculosis therapy. Main outcome measures: Serial examination, radiography, sputum culture, CD4 T-cell counts, plasma log10 HIV-RNA copy numbers. Results: Trends towards superior responses to tuberculosis treatment were evident in etanercept-treated subjects in body mass, performance score, number of involved lung zones, cavitary closure, and time to sputum culture conversion. Etanercept treatment resulted in a 25% increase in CD4 cells by week 4 (P = 0.1 compared with controls). The change in CD4 cell count was inversely related to the change in serum neopterin, a marker of macrophage activation. There was no effect on plasma HIV RNA. Conclusion: Etanercept can be safely administered during the initial treatment of pulmonary tuberculosis. Further studies are warranted to examine the effects of etanercept on T-cell numbers, activation and apoptosis in AIDS and tuberculosis.

Reconsidering Adjuvant Immunotherapy for Tuberculosis

BACKGROUNDnShortened regimens for treatment of pulmonary tuberculosis (TB) are urgently needed to facilitate its global eradication. Prolonged treatment is presently required to prevent relapse, which is thought to arise from persisting foci of semidormant infection contained within granulomas.nnnMETHODSnThe medical literature was reviewed to identify clinical trials of adjuvant TB immunotherapy, as well as other studies of the relationship between immune status and TB relapse or reactivation.nnnRESULTSnFour studies of therapeutic interferon indicated its inability to effectively augment the mycobactericidal capacity of lung macrophages. One randomized, placebo-controlled trial of therapeutic interleukin-2 found that it delayed the microbiologic response to treatment, whereas 2 controlled trials of anti-tumor necrosis factor (TNF) therapies (high-dose prednisolone and etanercept [a soluble TNF receptor]) found that these interventions significantly accelerated the response to treatment. Four retrospective studies were identified in which the response to TB therapy was accelerated and/or the relapse risk was reduced in persons with human immunodeficiency virus coinfection; one study reported that immune reconstitution syndrome due to use of antiretroviral therapy was associated with increased risk of relapse. Several studies indicated that granulomas may be efficiently targeted and disrupted by the anti-TNF antibody infliximab, apparently because of its ability to bind to cell-surface TNF and to induce apoptosis in TNF-expressing cells.nnnCONCLUSIONSnThese findings support the hypothesis that the granulomatous host response to TB may paradoxically protect sequestered mycobacteria from administered anti-TB therapy and that treatment may be improved by therapeutic disruption of granulomas. Clinical trials to test this hypothesis are warranted.

Therapeutic use of infliximab in tuberculosis to control severe paradoxical reaction of the brain and lymph nodes.

Paradoxical reactions are immune-mediated exacerbations of disease triggered by tuberculosis treatment. Paradoxical reactions involving the central nervous system may be life threatening. Infliximab (tumor necrosis factor antibody) profoundly inhibits cellular immune responses to Mycobacterium tuberculosis. We describe a case in which infliximab was used to control steroid-resistant tuberculosis paradoxical reaction involving the central nervous system.

Bactericidal Activity in Whole Blood as a Potential Surrogate Marker of Immunity after Vaccination against Tuberculosis

ABSTRACT The development of new tuberculosis (TB) vaccines will require the identification of correlates of human protection. This study examined the balance between immunity and virulence in a whole blood infection model in which intracellular mycobacterial survival was measured using BACTEC. In the blood of tuberculin-negative donors, counts of Mycobacterium tuberculosis H37Ra organisms fell by 0.14 log10 CFU during 96 h of whole blood culture, whereas counts of Mycobacterium bovis BCG, M. tuberculosis H37Rv, and a clinical TB isolates organisms increased by 0.13, 0.43, and 1.04 log10 CFU, respectively (P < 0.001), consistent with their relative virulence. Inhibition of tumor necrosis factor alpha by the addition of methylprednisolone or pentoxifylline or removal of CD4+ or CD8+ T cells by magnetic beads had deleterious effects on immune control of intracellular growth only in the blood of tuberculin-positive donors. Repeated vaccination of eight tuberculin-negative volunteers with M. bovis BCG resulted in a 0.3 log (50%) reduction in BCG CFU counts in the model compared to baseline values (P < 0.05). Three of the volunteers responded only after the second vaccination. These experiments indicate that whole blood culture may be used to measure immunity to M. tuberculosis and that further studies of repeated BCG vaccination are warranted.

Whole Blood Bactericidal Activity during Treatment of Pulmonary Tuberculosis

The timely evaluation of new drugs that can be used to shorten tuberculosis (TB) treatment will require surrogate markers for relapse. This study examined bactericidal activity against intracellular Mycobacterium tuberculosis in whole blood culture (whole blood bactericidal activity; WBA) during TB treatment. In the absence of chemotherapy, immune mechanisms in patient blood resulted in bacteriostasis, whereas administration of oral chemotherapy resulted in bacillary killing. Total WBA per dose was greater during the intensive phase of treatment than during the continuation phase (mean, -2.32 vs. -1.67 log(10) cfu-days, respectively; P<.001). Cumulative WBA throughout treatment was greater in subjects whose sputum cultures converted to negative by the eighth week of treatment than in those for whom conversion was delayed (mean, -365 vs. -250 log(10) cfu-days; P=.04) and correlated with the rate of decrease of sputum colony-forming unit counts during the first 4 weeks of treatment (P=.018), both of which are indicative of prognosis. These findings indicate that measurement of WBA may have a role in assessing the sterilizing activity of new anti-TB drugs.

A study of the immunology, virology, and safety of prednisone in HIV-1-infected subjects with CD4 cell counts of 200 to 700 mm(-3).

Adult Clinical Trials Group Study 349 examined the immunology, virology, and safety of 40 mg/d prednisone as an adjunct to antiretroviral therapy in 24 HIV-infected subjects with >200 CD4+ T cells/mm in a randomized placebo-controlled trial. After 8 weeks, median lymphocyte and CD4+ cell numbers increased >40% above baseline values (p =.08). No effect was observed on markers of cell activation or apoptosis, although the proportion of CD28+ CD8+ T cells increased (p =.006). Prednisone inhibited monocyte TNFalpha production without affecting T-cell responses to antigens or mitogens. Two subjects assigned to prednisone were subsequently found to have asymptomatic osteonecrosis of the hip. Many questions remain regarding the role of activation-induced sequestration and apoptosis as causes of progressive CD4+ T-cell loss in AIDS. The potential role of corticosteroids as tools to examine this question will be limited by concerns regarding their toxicity; however, further studies of other agents to limit cellular activation in AIDS are warranted.

Inhibition of Isoniazid-Induced Expression of Mycobacterium tuberculosis Antigen 85 in Sputum: Potential Surrogate Marker in Tuberculosis Chemotherapy Trials

ABSTRACT Mycobacterium tuberculosis antigen 85 is induced in vitro by isoniazid (INH); its sustained induction in sputum during tuberculosis (TB) therapy predicts relapse. In this trial, rifampin or rifalazil inhibited the induction of sputum antigen 85 by INH in a dose-dependent fashion. This approach may facilitate the evaluation of new TB drugs.

Adult tuberculosis in the 21st century: pathogenesis, clinical features, and management.

This article reviews the significant advances in the past year in the basic and clinical aspects of adult tuberculosis (TB). Further research has deepened our understanding of host susceptibility and resistance mechanisms, including cytotoxicity, apoptosis, and antimicrobial polypeptides such as granulysin. Studies have confirmed the effects of HIV infection on risk of disease and disease manifestations, and have defined the effects of HIV on TB transmission. Recent studies also indicate a possible role for extended treatment of active disease and latent infection in HIV-1 infected individuals. Multidrug-resistant disease has been reported on every continent; rapid molecular approaches to the simultaneous diagnosis of TB and detection of rifampin resistance may facilitate prompt initiation of treatment. TB remains one of the major problems in global health.

Immunotherapy for Tuberculosis and Other Mycobacterial Infections

At least one-fourth of the world’s population is infected with Mycobacterium tuberculosis, resulting in nearly 4 million deaths worldwide each year, more than any other single pathogen. In some areas, such as southern Africa and southeast Asia, tuberculosis case rates have approached 200 cases per 100,000 persons/year, or nearly 0.2% annually (1), despite vaccination with M. bovis bacille Calmette-Guerin (BCG) and increased access to chemotherapy. In other regions, including eastern Europe and Russia, multidrug-resistant (MDR) infection has emerged as a major threat to public health (2). As a consequence, there is greater urgency to define the factors involved in host resistance to mycobacterial infection and to evaluate their potential therapeutic application in clinical trials.