Polymorphisms of interferon-gamma and interferon-gamma receptor 1 genes and pulmonary tuberculosis in Koreans

BACKGROUND AND OBJECTIVE: Many genetic variations are thought to be risk factors for the development of pulmonary tuberculosis (TB). The association of interferon-gamma (IFN-gamma) and IFN-gamma receptor 1 (IFN-gammaR1) gene polymorphisms with pulmonary TB is controversial. This study examined the association between IFN-gamma and IFN-gammaR1 gene polymorphisms and pulmonary TB among Koreans. METHODS: Eighty patients with culture-confirmed pulmonary TB and 80 controls were studied. Polymorphisms of the IFN-gamma gene at position +874 were determined using the amplification refractory mutation system PCR assay, and the IFN-gammaR1 gene was genotyped at positions -611, -270, -56 and +95 employing matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using genomic DNA. RESULTS: The genotype and allele frequencies of the IFN-gamma and IFN-gammaR1 gene polymorphisms did not differ significantly between the patients with pulmonary TB and controls. CONCLUSIONS: The IFN-gamma and IFN-gammaR1 gene polymorphisms do not appear to be responsible for host susceptibility to pulmonary TB in the Korean population.     

Clinical analysis of pulmonary tuberculosis in association with corticosteroid therapy

OBJECTIVE: Due to the increased incidence of pulmonary tuberculosis in association with corticosteroid therapy during the last five years in our associated hospitals, we studied the clinical characteristics of these patients. PATIENTS: Fourteen cases of pulmonary tuberculosis were collected which occurred in association with corticosteroid drugs in our associated hospitals during the last 10 years; four patients (2.1%) from April 1991 to March 1996 and 10 patients (4.3%) from April 1996 to March 2001. RESULTS: The average age of the 14 patients was 74.1 years old and the male:female ratio was 9:5. Regarding underlying diseases, respiratory diseases (7 patients) were the most frequent and a past history of pulmonary tuberculosis was recognized in six patients. The duration of corticosteroid administration ranged from two months to seven years and the total dose of corticosteroids ranged from 1.20 g to 12.05 g. Pulmonary tuberculosis was detected by chance during a health examination in eight patients and radiological findings showed an infiltration shadow without cavity located in a portion other than the predominant location in four patients. A microbiological examination was smear positive in eight patients but tolerance was not shown to any antituberculous drugs. The prognosis was poor because the mortality rate was high, but the cause of death was not related to the progress of pulmonary tuberculosis. CONCLUSION: Careful observation of patients is considered to be important because pulmonary tuberculosis in association with corticosteroid drugs was found among inpatients, there was no relationship to the total dose or duration of administration of corticosteroid drugs, there were no clinical symptoms, and the patients exhibited atypical radiographic findings.     

Regional deposition of aerosolized interferon-gamma in pulmonary tuberculosis

STUDY OBJECTIVES: Aerosol interferon-gamma (IFN-gamma) is a potential immunomodulator in the treatment of pulmonary tuberculosis (TB). Previous investigations demonstrated conversion of sputum smears in five patients with multidrug-resistant TB after 12 treatments over 1 month, and induction of signaling molecules in 10 of 11 drug-sensitive TB patients using BAL. The objective of the current study was to evaluate particle size and deposition pattern in patients with TB receiving aerosol IFN-gamma treatment. DESIGN: Particle size was determined with a cascade impactor, and deposition of IFN-gamma mixed with (99m)Tc-labeled human serum albumin was assessed using a gamma camera. Local levels of IFN-gamma were measured in BAL using enzyme-linked immunosorbent assays. Study patients/intervention: Fourteen patients with pulmonary TB received IFN-gamma aerosol (500 micro g) for 12 treatments in addition to antimycobacterial therapy with BAL before and after IFN-gamma aerosol treatment. Eight patients with minimal-to-moderate parenchymal involvement underwent deposition studies. Deposited (99m)Tc-labeled IFN-gamma aerosol was partitioned between upper airways and lungs using attenuation correction measurements. (133)Xe equilibrium scanning, (133)Xe washout, and (99m)Tc- macroaggregate injection defined regional lung volume, ventilation, and perfusion. RESULTS: Upper airway deposition was significant often exceeding lung deposition (53.9 +/- 7.09 micro g vs 35.8 +/- 2.73 micro g, respectively [mean +/- SE]). IFN-gamma levels measured in BAL fluid were significantly increased with aerosol treatment (0.83 +/- 0.43 micro g before vs 24.76 +/- 8.71 micro g after, p 相似文献   

Clinical analysis of pulmonary tuberculosis in association with corticosteroid therapy

In the last five years, five patients (three males and two females) among a total of 162 patients (3.1%) ranging from 63 to 79 years old developed pulmonary tuberculosis during the long-term corticosteroid therapy. The underlying diseases of these cases were pulmonary fibrosis in two, polyarteritis nodosa in one, RPGN + pulmonary bleeding in one, and mycosis fungoides in one. The total corticosteroid dose used until the clinical diagnosis of pulmonary tuberculosis was 1.16 g to 5.60 g and the term of administration was two to nine and a half months. Other immunosuppressive drugs were administered to two patients. Though chemoprophylaxis with INH was done in two patients for three months, it was impossible to prevent the development of pulmonary tuberculosis. Since almost all patients except one complained no symptoms at the onset, the follow-up with chest roentgenograms seemed to be most important during corticosteroid therapy, and in fact, four patients were detected by the follow-up. Antituberculous chemotherapy was effective in four patients but was not carried out for one patient due to the delay in the diagnosis. Careful clinical observation, such as by chest roentgenograms, seems to be appropriate for the early diagnosis and treatment of pulmonary tuberculosis in patients on corticosteroid therapy.     

Clinical analysis of pulmonary tuberculosis detected during follow-up of other underlying diseases

OBJECTIVE: The objects of this study were to analyze clinically the outpatients and inpatients who were diagnosed as pulmonary tuberculosis during the follow-up of other underlying diseases at our affiliated hospitals and to review the past problems and to discuss how to improve the situation. METHODS: Sixty five outpatients or inpatients diagnosed as pulmonary tuberculosis during the follow-up of other underlying diseases were collected from 508 patients with pulmonary tuberculosis at our affiliated hospitals over the past 10 years. RESULTS: The proportion of elderly patients over 65 years old among 65 index cases was significantly higher as compared to the control group. Forty three of these index patients were outpatients and 22 were inpatients. The most frequent underlying diseases excluding respiratory diseases were malignant diseases followed by diabetes mellitus, gastrointestinal diseases and psychosomatic diseases in order. Pulmonary tuberculosis without clinical symptoms was detected by periodic chest X-ray in 21 cases (32%). There were some severe TB cases caused by the doctor's delay who were followed for malignant or psychosomatic diseases. CONCLUSION: Although many doctors except for respiratory specialists tended to pay attention to pulmonary tuberculosis as a possible complication during periodic health examination, further intensive education regarding pulmonary tuberculosis is required for doctors who treat malignant or psychosomatic diseases at special hospitals because TB patients who were smear positive when they were detected may cause outbreak of tuberculosis in the hospital.     

Plasma granulysin levels and cellular interferon-gamma production correlate with curative host responses in tuberculosis, while plasma interferon-gamma levels correlate with tuberculosis disease activity in adults

Granulysin is a recently identified cytolytic protein which is expressed by human cytotoxic T-lymphocytes and natural killer (NK)-cells, and has broad antimicrobial and tumoricidal activity. Circulating granulysin levels are associated with T- and NK-cell activity, and may thus reflect protection-associated cellular immune responses. In a case-control study in Indonesia, a highly tuberculosis (TB)-endemic country, we therefore determined plasma granulysin levels in adults with active pulmonary TB before, during, and after TB treatment, both in mild/moderate-TB and advanced-TB patients, and compared these to healthy neighbourhood controls. Adults with active pulmonary TB had significantly lower plasma granulysin levels compared to controls. After 2 months of anti-TB therapy, levels in TB patients had significantly increased, reaching values similar to those in controls. Plasma granulysin levels further increased after completion of TB therapy, being significantly higher than those in controls. Plasma granulysin levels correlated inversely with TB disease activity but not with TB disease severity. In contrast, plasma interferon-gamma (IFN-gamma) levels were significantly higher in active TB cases than in controls, normalised during treatment and correlated with both TB disease activity and TB disease severity. At the cellular level, granulysin and IFN-gamma expression both correlated inversely with disease activity. Interestingly, granulysin was predominantly expressed by IFN-gamma negative T-cells, suggesting that the cellular sources of IFN-gamma and granulysin in TB are partly non-overlapping. The observation that plasma granulysin levels and cellular IFN-gamma production correlate with curative host responses in pulmonary tuberculosis points to a potentially important role of granulysin, next to IFN-gamma, in host defence against M. tuberculosis.     

Cellular interferon-gamma based assay for diagnosis of pulmonary tuberculosis

A major breakthrough in recent years has been the development of an in vitro assays that measure T-cell release of interferon gamma (IFN-gamma) in response to stimulation with antigens specific to Mycobacterium tuberculosis (MTB) such as early secreted antigenic target 6 (ESAT6) and culture filtrate protein 10 (CFP10). This study aimed at evaluating the diagnostic potential of IFN-gamma in vitro production assay for diagnosis of pulmonary tuberculosis. The study included 40 patients from Abbasia Chest Hospital, Cairo, Egypt. Thirty patients had the provisional clinical and radiological diagnosis of pulmonary tuberculosis (TB), twenty of them had positive acid fast (AF) sputum smears (group I), and ten had negative smears (group II). Bacteriological confirmation of TB was based on cultivation on L.J solid media (group I & II), and by BACTEC radiometric assay (group II). Ten patients with non tuberculous chest diseases were also included as a control group (group III). Effector T cells, within the peripheral blood mononuclear cells, which secrete IFN-gamma in response to stimulation by antigens specific for MTB (ESAT-6 and CFP-10) were analyzed in all subjects using a commercially available assay based on the enzyme linked immunospot technique. We demonstrated that 24 out of 30 (80%) suspected tuberculous patients were bacteriologically confirmed based on positive AF smears and/or culture. In vitro IFN-gamma release assay was positive in 22 of them giving a sensitivity of 91.7%. In the remaining 6 who were not confirmed bacteriologically, the assay showed positive results in 4 (66.7%) of them. Based on bacteriological diagnosis as the gold standard for diagnosis of pulmonary TB, the specificity of the assay was found to be 75%. However the assay results were negative in all non tuberculous patients (group III). It is concluded that the used in vitro IFN-gamma release assay has the potential to become a useful diagnostic tool for active tuberculosis.     

Rifampin levels, interferon-gamma release and outcome in complicated pulmonary tuberculosis

Factors that relate to medium-term outcome in patients with pulmonary tuberculosis (PTB) who have completed the 2-month intensive phase of treatment are incompletely understood. The relationship between in vitro production of interferon-gamma (IFN-gamma), interleukins (ILs)-5 and -10 and drug levels determined after 2 months of drug therapy, to outcome at 24 months was studied prospectively. Cytokine concentrations were determined from culture supernatants after stimulation of whole blood with purified protein derivative (PPD) of Mycobacterium tuberculosis. Plasma concentrations of rifampin, isoniazid, pyrazinamide and ethambutol were determined by high-performance liquid chromatography. The treatment failure and relapse free survival probability was 0.54 (95% CI: 0.40-0.67) at 24 months. In multivariate analysis of parameters at 2 months the strongest positive associations with disease free survival were IFN-gamma response to PPD (p=0.002) and serum creatinine (p=0.001). Drug concentrations were not associated with outcome although rifampin exposure correlated with IFN-gamma response to PPD (p=0.0132). These data suggest that the ability to mount a recall immune response to M. tuberculosis may influence treatment outcome. The data support the idea to identify persons at risk of a poor treatment outcome by monitoring of the in vitro response to tuberculosis antigens.     

Usefulness of whole-blood interferon-gamma assay and interferon-gamma enzyme-linked immunospot assay in the diagnosis of active pulmonary tuberculosis

PURPOSES: The aim of this study was to evaluate the usefulness of the whole-blood interferon-gamma assay (enzyme-linked immunosorbent assay [ELISA]) and interferon-gamma enzyme-linked immunospot assay (ELISPOT) based on early secretory antigenic target 6 and culture filtrate protein 10 in the diagnosis of active pulmonary tuberculosis (TB) in routine clinical practice. METHOD: We conducted a prospective study enrolling 144 participants with suspected pulmonary TB in a tertiary referral hospital in Seoul, South Korea, to investigate the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these tests. Clinical assessment, tuberculin skin test (TST), whole-blood interferon-gamma ELISA (QuantiFERON-TB Gold [QFT-G]; Cellestis Ltd; Victoria, Australia), and an ELISPOT assay (T SPOT.TB; Oxford Immunotec; Oxford, UK) were performed. Test results were compared with the final confirmed diagnoses. RESULTS: Active pulmonary TB was diagnosed in 67 of 144 participants (47%). Sensitivities of QFT-G and T SPOT.TB for active pulmonary TB were 89% (95% confidence interval [CI], 79 to 96%) and 92% (95% CI, 83 to 97%), respectively; and specificities were 49% (95% CI, 37 to 61%) and 47% (95% CI, 36 to 59%). NPVs of QFT-G (84%; 95% CI, 69 to 93%) and T SPOT.TB (87%; 95% CI, 73 to 96%) were higher than that of TST (64%; 95% CI, 51 to 76%) [p = 0.001 and p < 0.001, respectively]. CONCLUSION: High NPVs of QFT-G and T SPOT.TB for the diagnosis of active TB suggest the supplementary role of these tests for the diagnostic exclusion of active TB, although the low PPV limits their usefulness in routine clinical practice in South Korea, where the prevalence of latent TB infection is considerable.     

Relationship between whole-blood interferon-gamma responses and the risk of active tuberculosis

We have analyzed the relationship between the responses to the diagnostic method for Mycobacterium tuberculosis (Mtb) infection, QuantiFERON-TB Gold (QFT-G), and the risk of developing active tuberculosis (TB). Contacts under 42 years old who were exposed to a patient with infectious pulmonary TB were tested using QFT-G during an investigation. Among 172 contacts, 111 (64.5%) were QFT-G positive. All subjects were evaluated for active TB by chest X-ray examination and, if needed, by CT scan at the time of the QFT-G test and 39 were diagnosed with active TB based on radiological abnormalities consistent with TB. Of these, 35 (89.7%) were QFT-G positive. Statistically the geometric mean of interferon-gamma (IFN-gamma) production levels of the active TB group was significantly larger than that of the latent TB infection group (p=0.013). The results of the multivariate analysis clearly showed that a combined parameter of ESAT-6 and CFP-10 significantly contributes to disease risk for the infected subjects. Our results suggest that subjects with high levels of IFN-gamma production in response to either ESAT-6 and/or CFP-10 in the QFT-G test have a higher possibility of developing active TB than QFT-G positive subjects with lower levels of IFN-gamma.     

Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis

RATIONALE: Interferon-gamma (IFN-gamma) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN-gamma signaling pathway that predispose to severe mycobacterial disease, but the relevance of polymorphism within these genes to the common phenotype of tuberculosis remains unclear. METHODS: A total of 1,301 individuals were included in a large, detailed study of West African populations with pulmonary tuberculosis. We investigated disease association with the genes encoding IFN-gamma and its receptor subunits (IFNG, IFNGR1, and IFNGR2). RESULTS: Within the IFNG gene, two promoter variants showed evidence of novel disease association: -1616GG (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.11-2.00; p = 0.008) and +3234TT (OR, 1.40; 95% CI, 1.09-1.80; p = 0.009). The +874AA genotype was not significantly more frequent among cases over control subjects (OR, 1.16; 95%CI, 0.89-1.51; p = 0.25). In addition, novel disease association was also found with the -56CC genotype of the IFNGR1 promoter (OR, 0.75; 95% CI, 0.57-0.99; p = 0.041). No disease association was seen with the IFNGR2 locus. CONCLUSIONS: These results provide evidence of a significant role for genetic variation at the IFNG locus and provide detailed understanding of the genetic mechanisms underlying this association. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN-gamma production and responsiveness influences the risk of developing tuberculosis.     

Pathogenetic therapy in pulmonary tuberculosis

Clinico-biochemical comparisons with an account of the peculiar characteristics of the tuberculosis process showed that it was advisable to use antioxidants as antifibrotic pathogenetic agents. The most pronounced effect was observed when combinations of two antioxidants or one antioxidant with lidase were applied.