Interferon-γ Release Assays for Diagnosing Mycobacterium tuberculosis Infection in Renal Dialysis Patients

Background and objectives: End-stage renal disease (ESRD) patients are at high risk for tuberculosis (TB). IFN-γ release assays that assess immune responses to specific TB antigens offer potential advantages over tuberculin skin testing (TST) in screening such patients for Mycobacterium tuberculosis infection. This study sought to determine whether IFN-γ release assay results are more closely associated with recent TB exposure than TST results.Design, setting, participants, and measures: Prospective cohort investigation of patients at a hemodialysis center with a smear-positive case of TB. Patients without a history of TB underwent initial and repeat testing with TST, and with the IFN-γ assays QuantiFERON-TB Gold® (QFT-G) and ELISPOT test. Outcome measures included the prevalence of positive test results, identification of factors associated with positive results, and test result discordance.Results: A total of 100 (47% foreign born; median age, 55 yr; age range, 18 to 83 yr) of 124 eligible patients were enrolled. Twenty-six persons had positive TST results, 21 had positive QFT-G results, and 27 had positive ELISPOT results. Patients with TB case contact were likely to have a positive QFT-G result (P = 0.02) and ELISPOT results (P = 0.04), whereas TB case contact was not associated with positive TST results (P = 0.7). Positive TST results were associated with foreign birth (P = 0.04) and having had a TST in the previous year (P = 0.04).Conclusions: Positive IFN-γ assay results were more closely associated with recent TB exposure than were positive TST results. QFT-G and ELISPOT might offer a better method for detecting TB infection in ESRD patients.More than 300,000 persons in the United States with end-stage renal disease (ESRD) currently require renal replacement therapy (1). These patients are at increased risk for a variety of infections. The basis for their underlying immune dysfunction is not completely understood but thought to be mediated by uremia (2). Renal failure patients are at 8 to 25 times higher risk for tuberculosis (TB) than the general population (3–5). TB disease in these patients can be difficult to diagnose, as it is frequently extrapulmonary and insidious in onset (6). Recommendations for screening dialysis patients for latent Mycobacterium tuberculosis infection (LTBI) exist to decrease transmission of TB in this setting of highly susceptible patients (7).Despite such recommendations, screening dialysis patients for latent TB infection can be difficult. Their underlying immune suppression raises the likelihood of false-negative TB skin test (TST) results and makes interpretation of negative results unreliable. Dialysis patients have been shown to have significant rates of cutaneous anergy to antigens, such as Candida, mumps, or tetanus (8,9). Furthermore, as in immunocompetent populations, the TST can be falsely positive in persons with a history of previous nontuberculous mycobacterium infection or vaccination with bacillus Calmette-Guerin (BCG) (10).Newly developed blood tests might offer improved ways of screening ESRD patients for LTBI. The QuantiFERON-TB Gold® test (QFT-G) measures production of IFN-γ by sensitized lymphocytes after whole blood is stimulated with specific TB antigens. It became commercially available in the United States following approval by the Federal Drug Administration in May 2005. The enzyme-linked immuno-spot assay (ELISPOT) is a diagnostic platform that enumerates the number of reactive T lymphocytes releasing IFN-γ in the presence of TB antigens. Both of these technologies can be used to assess immune response to Culture Filtrate Protein 10 (CFP-10) and Early Secretory Antigen 6 (ESAT-6). These antigens are encoded on the RD-1 portion of the M. tuberculosis genome, and are not found in BCG strains or most nontuberculous mycobacterium. Accordingly, these tests are more specific for LTBI than the TST, which relies on purified protein derivative (11). To date, there has been limited evaluation of QFT-G and ELISPOT in screening immunosuppressed populations for TB, including those with ESRD.In October 2003, we were notified of a TB case in a dialysis center in southern California. We evaluated patients at the dialysis center and assessed the utility of using the IFN-γ assays during a TB-contact investigation. We compared the results of IFN-γ assays and TST and identified factors associated with positive test results and test result discordance.     

Comparison of T-Cell Interferon-γ Release Assays for Mycobacterium tuberculosis-Specific Antigens in Patients with Active and Latent Tuberculosis

Through the use of QuantiFERON-TB Gold, a commercial IFN-γ assay, we compared differences in quantitative T-cell responses to Mycobacterium tuberculosis (MTB)-specific antigens [QuantiFERON TB-2G (QFT-2G)] between patients with active tuberculosis (TB) disease and those with latent TB infection (LTBI). The patient group consisted of 180 patients with active TB disease (culture-positive for MTB) and 50 screening contacts with LTBI-positive response to the QFT-2G test. We prospectively performed a tuberculin skin test (TST) and a QFT-2G test for all subjects. The median IFN-γ levels upon the application of both antigens, ESAT-6 and CFP-10, were significantly higher in patients with active TB disease than in those with LTBI. A combined positive response to both antigens occurred at a higher rate in patients with active TB disease than in those with LTBI. There were no significant relationships between the quantitative responses of IFN-γ to both antigens and the maximum induration on TST in both patient groups. We demonstrated significant differences in the quantitative responses of IFN-γ to MTB between patients with active TB disease and those with LTBI in this study. However, there was an overlap in the IFN-γ levels between active TB disease and LTBI groups. Therefore, it would be difficult to use the QFT-2G test to completely discriminate active TB disease from LTBI.     

Interferon β-1b Therapy in Chronic Viral Dilated Cardiomyopathy—Is There a Role for Specific Therapy?

BackgroundMyocardial biopsy can be used for the detection of viral genome in dilated cardiomyopathy (DCM). Pilot studies have previously reported beneficial effects on clinical outcome and safety of an antiviral therapy using interferon β-1b in chronic viral DCM.Methods and ResultsMyocardial biopsies were taken from patients with DCM. Using polymerase chain reaction and Southern Blot analysis, viral genome could be detected in 49% of patients. In 42 patients with viral infection, off-label use with interferon β-1b was initiated. A further 68 patients formed the control group. The outcome was evaluated after follow-up with echocardiography, exercise electrocardiogram, and New York Heart Association class. A total of 81 men and 29 women with a median left ventricular ejection fraction of 34% were included. The follow-up period was 36 months. In 33 (79%) patients with interferon β-1b treatment, minor adverse reactions occurred, but no major adverse events were reported. No significant benefit for interferon β-1b treatment on clinical outcome could be detected during follow-up.ConclusionsOff-label use with interferon β-1b in patients with viral DCM is feasible and safe under routine clinical practice. Concerning the herein evaluated clinical outcome parameters, promising results from pilot studies could not be confirmed. High prevalence of parvovirus B19 (92%) might influence the results.     

Successful Treatment With Novel Triple Drug Combination Consisting of Interferon-γ, Interferon Alfacon-1, and Ribavirin in a Nonresponder HCV Patient to Pegylated Interferon Therapy

Despite major advances in therapy of hepatitis C over the past decade, nearly half of the patients treated with the currently available regimens do not clear the virus. Therefore, there is a large unmet need for more effective therapy for patients who have failed pegylated interferon plus ribavirin therapy. We describe a case of a HCV genotype 1b patient who had failed previous combination therapies of interferon plus ribavirin and pegylated interferon plus ribavirin and was subsequently successfully treated with a novel triple drug combination consisting of interferon-γ plus interferon alfacon plus ribavirin with the outcome of a sustained virologic response. This triple drug therapy combination could be an option for patients who have failed therapies with currently available pegylated interferons plus ribavirin. Prospective randomized studies are required to evaluate the effectiveness and tolerability of this regimen in this patient population.     

Secreted Phosphoprotein 1 Promoter Genetic Variants Are Associated with the Response to Pegylated Interferon α Plus Ribavirin Combination Therapy in Egyptian Patients with Chronic Hepatitis C Virus Infection

Background/Aims

The T-helper 1 (TH1) immune reaction is essential for the eradication of hepatitis C virus (HCV) during pegylated interferon α (PEG-IFN-α)- and ribavirin (RBV)-based therapy in chronic HCV patients. Secreted phosphoprotein 1 (SPP1) was shown to be a crucial cytokine for the initiation of a TH1 immune response. We aimed to investigate whether SPP1 single nucleotide polymorphisms (SNPs) may influence sustained virological response (SVR) rates.

Methods

Two SNPs in the promoter region of SPP1 at the −443 C>T and −1748 G>A loci were genotyped in 100 patients with chronic HCV genotype 4 infection using a TaqMan SNP genotyping assay.

Results

Sixty-seven patients achieved a SVR, and 33 patients showed no SVR. Patients carrying the T/T genotype at the −443 locus showed a significantly higher SVR rate than those carrying the C/T or C/C genotype (83.67% vs 50.98%, p<0.001). At the −1748 locus, the SVR rate was significantly higher in patients with the G/G genotype than in those with the A/A genotype (88.89% vs 52.63%, p=0.028) and in patients with the G/A genotype than in those with the A/A genotype (85.29% vs 52.63%, p=0.001).

Conclusions

SPP1 SNPs at −443 C>T and −1748 G>A loci may be useful markers for predicting the response to PEG-IFN-α-2b plus RBV therapy in Egyptian patients with chronic HCV genotype 4 infection.