Diagnosing tuberculosis infection in the 21st century: new tools to tackle an old enemy

The century-old tuberculin skin test (TST) was until recently the only means of diagnosing latent tuberculosis infection (LTBI). Recent advances in mycobacterial genomics and human cellular immunology have resulted in two new blood tests that detect tuberculosis infection by measuring in vitro T-cell interferon (IFN)-gamma release in response to two unique antigens that are highly specific for Mycobacterium tuberculosis but absent from bacille Calmette-Guérin (BCG) vaccine and most nontuberculous mycobacteria. One assay, the enzyme-linked immunospot (ELISpot) [T-SPOT.TB; Oxford Immunotec; Oxford, UK] enumerates IFN-gamma-secreting T cells, while the other assay measures IFN-gamma concentration in supernatant by enzyme-linked immunosorbent assay (ELISA) [QuantiFERON-TB Gold; Cellestis; Carnegie, Australia]. A large and growing clinical evidence base indicates that both tests are more specific than the skin test because they are not confounded by prior BCG vaccination. In active tuberculosis, ELISA has similar sensitivity to the skin test, while ELISpot is significantly more sensitive. Current cross-sectional evidence suggests that for diagnosis of LTBI, sensitivity of ELISA is similar to TST, while ELISpot appears more sensitive. High specificity will enable clinicians to avoid unnecessary preventive treatment in BCG-vaccinated persons without infection who commonly have false-positive TST results. High sensitivity could enable accurate targeting of preventive treatment to patients with infection at the highest risk of progression to active tuberculosis who frequently have false-negative TST results due to impaired cellular immunity. However, longitudinal studies are needed to define the predictive value of positive blood test results for progression to tuberculosis.     

Risk of progression to active tuberculosis among foreign-born persons with latent tuberculosis

BACKGROUND: Increased risk for tuberculosis (TB) disease has been identified in foreign-born persons in the United States, particularly during the first 5 years after their arrival in the United States. This could be explained by undetected TB disease at entry, increased prevalence of latent TB infection (LTBI), increased progression from LTBI to TB, or a combination of these factors. METHODS: We performed a cluster analysis of TB cases in Boston and a case-control study of risk factors for TB with an unclustered isolate among Boston residents with LTBI to determine whether such persons have an increased risk for reactivation of disease. RESULTS: Of 321 case patients with TB seen between 1996 and 2000, 133 isolates were clustered and 188 were not. In multivariate analysis, foreign birth was associated with an unclustered isolate (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2 to 3.8; p < 0.01), while being a close contact of a TB case was negatively associated (OR, 0.22; 95% CI, 0.07 to 0.73; p = 0.02). When 188 TB patients with unclustered isolates were compared to 188 age-matched control subjects with LTBI, there was no association between the occurrence of TB and foreign birth (OR, 0.71; 95% CI, 0.42 to 1.3); among foreign-born persons, there was no association between the occurrence of TB and being in the United States 相似文献   

Updated evaluation of the cost-effectiveness of lung volume reduction surgery

BACKGROUND: The National Emphysema Treatment Trial, a randomized clinical trial of lung volume reduction surgery (LVRS) vs medical therapy for severe emphysema, included a prospective economic analysis. We present an updated analysis of cost-effectiveness with 1-year additional follow-up data. METHODS: Following pulmonary rehabilitation, 1,218 patients at 17 medical centers were randomized to receive LVRS or continued medical treatment. The cost-effectiveness of LVRS vs medical therapy was calculated over the duration of the trial (January 1998 to December 2003) and estimated at 10 years using modeling based on observed trends in survival, cost, and quality of life. RESULTS: The cost-effectiveness of LVRS vs medical therapy was $140,000 per quality-adjusted life-year (QALY) gained (95% confidence interval, $40,155 to $239,359) at 5 years, and was projected to be $54,000 per QALY gained at 10 years. In subgroup analysis, the cost-effectiveness of LVRS in patients with upper-lobe emphysema and low exercise capacity was $77,000 per QALY gained at 5 years, and was projected to be $48,000 per QALY at 10 years. Compared to the initial results, the updated results are similar for the overall cohort but vary substantially for the subgroups. CONCLUSIONS: LVRS is costly relative to other health-care programs during the time horizon when costs and outcomes are known. The extended follow-up period offers more certainty regarding the long-term value and economic impact of this procedure.     

Use of an interferon-gamma release assay to diagnose latent tuberculosis infection in foreign-born patients

BACKGROUND: The tuberculin skin test (TST) has a low specificity in the setting of bacille Calmette-Guérin (BCG) vaccination. Interferon-gamma release assays (IGRAs) appear to be more specific but have not been validated in this population under routine clinical conditions. We sought to validate the routine clinical use of the T-SPOT.TB test (Oxford Immunotec; Oxford, UK), an IGRA, in a predominantly foreign-born population with a high rate of BCG vaccination. METHODS: We compared the TST and the T-SPOT.TB test in 96 subjects at a New York City Department of Health tuberculosis clinic. We aimed to determine which test better predicted being a close contact of a case of active tuberculosis, a surrogate for latent tuberculosis infection. RESULTS: A positive T-SPOT.TB test result was strongly associated with being a close contact of a case of active tuberculosis after adjustment for potential confounders (adjusted odds ratio, 2.9; 95% confidence interval, 1.1 to 7.3; p = 0.03). A positive TST result was associated with being a contact only in subjects without BCG vaccination (p = 0.02). The T-SPOT.TB test was more specific for being a close contact than the TST (p < 0.001). Specificity in BCG-vaccinated subjects was 3% for the TST compared with 70% for the T-SPOT.TB test (p < 0.001). CONCLUSIONS: The T-SPOT.TB test is superior in routine clinical use to the TST for identifying high-risk individuals among foreign-born populations with high rates of BCG vaccination.     

Health-related quality of life trajectories among adults with tuberculosis: differences between latent and active infection

BACKGROUND: Tuberculosis (TB) remains a public health threat with significant annual impacts on morbidity and mortality. However, few studies have examined the impact of active and latent TB infection (LTBI) on health-related quality of life (HRQL). METHODS: Patients with recently diagnosed active TB or LTBI patients were administered the Short Form-36 (SF-36) and the Beck depression inventory (DI) at baseline, 3 months, and 6 months. Mixed-effect linear regression was used to compare the trajectory of HRQL over time in the two patient groups after adjusting for potential confounders. Ordinal logistic regression was used to determine the relationship between changes in HRQL of at least the minimal important difference. RESULTS: One hundred four active TB and 102 LTBI patients participated. At baseline, participants with active TB had significantly lower SF-36 mean domain and component scores (4 to 12 points lower, p < 0.03) and higher mean Beck DI scores (4 points higher, p < 0.0001) when compared to LBTI participants. In the responder analysis, those with active TB were associated with reporting improved scores at 6 months of at least the minimal important difference in vitality (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.3 to 5.6), role physical (OR, 3.1; 95% CI, 1.4 to 6.5), mental component score (OR, 3.2; 95% CI, 1.5 to 6.9), social functioning (OR, 11.1; 95% CI, 3.8 to 33), and role emotional (OR, 2.7; 95% CI, 1.2 to 6.0). CONCLUSIONS: Active TB patients had large improvements in most HRQL domains by 6 months. However, when compared to LTBI participants and US norms, HRQL was still low at completion of therapy.     

Factors associated with failure to complete isoniazid treatment for latent tuberculosis infection in Rhode Island

BACKGROUND: The treatment of latent tuberculosis infection (LTBI) is essential for tuberculosis elimination in the United States, but the major limitation is poor adherence to therapy. To aid the design of targeted adherence interventions, we investigated the factors associated with noncompletion of isoniazid (INH) therapy for LTBI. METHODS: A retrospective analysis of patients with who failed to complete vs those who completed 9 months of INH therapy at the RISE TB Clinic (Miriam Hospital; Providence, RI) in 2003 was performed. Factors associated with treatment noncompletion were examined using univariate and multiple logistic regression analysis. RESULTS: Of 845 patients with LTBI, 690 patients (81.6%) initiated INH therapy, of whom 426 patients (61.7%) completed therapy, and 246 patients (35.6%) were lost to follow-up. Treatment was discontinued in 18 patients (2.6%). Patients who failed to complete therapy were younger (mean age, 30.6 vs 33.8 years, respectively; p = 0.006), and were more likely to be uninsured (42.9% vs 29.8%, respectively; p = 0.0004), to be postpartum (66.7% vs 37.3%, respectively; p = 0.043), and to report treatment side effects (54.8% vs 30.1%, respectively; p < 0.0001). Reported treatment side effects (odds ratio [OR], 3.6; 95% confidence interval [CI], 2.2 to 6.2) and lack of medical insurance (OR, 1.7; 95% CI, 1.1 to 2.7) were each associated with treatment noncompletion in a model including both. Also, pregnant women were more likely than nonpregnant women to fail to initiate INH treatment (52.1% vs 14.7%, respectively; p < 0.0001). CONCLUSIONS: LTBI patients who are young, pregnant or postpartum, uninsured, and/or report treatment side effects may require additional case management to improve INH treatment completion rates.     

The effect of previous tuberculin skin test on the follow-up examination of whole-blood interferon-gamma assay in the screening for latent tuberculosis infection

BACKGROUND: A two-step procedure using a tuberculin skin test (TST) followed by an interferon (IFN)-gamma assay in cases in which the TST result is positive has been advocated to screen for latent tuberculosis infection. However, TST could also boost the in vitro immune response. In this study, we evaluated the effect of TST on the results of the IFN-gamma assay. METHODS: Our study included 84 health-care workers who had been working in the department of pulmonary medicine for > 1 year. First, a whole-blood IFN-gamma assay was performed, and then the TST was applied. Two to 4 weeks later, a follow-up IFN-gamma assay was performed. A commercially available IFN-gamma assay (QuantiFERON-TB GOLD; Cellestis Ltd; Carnegie, VIC, Australia) was used. RESULTS: Valid TST results were available in 82 individuals because 2 participants refused to undergo the TST after the IFN-gamma assay. The TST result was positive in 36 of 82 participants (42.7%), and the IFN-gamma assay was positive in 16 of 82 participants (19.5%). The overall agreement between the two tests was 67.5% (kappa = 0.31; 95% confidence interval, 0.22 to 0.40). The IFN-gamma levels increased significantly from 0.05 to 0.19 (p = 0.011), and 3 of 18 participants (16.7%) had conversion of their IFN-gamma assay results in the TST-positive group. However, in the TST-negative group, the IFN-gamma levels did not change after the TST. CONCLUSION: The agreement between the results of the TST and the IFN-gamma assay was low, and IFN-gamma level could be influenced by the TST, in the TST-positive population, when a follow-up IFN-gamma assay is performed 2 to 4 weeks later.     

The effect of neonatal bacille Calmette-Guérin vaccination on purified protein derivative skin test results in Canadian aboriginal children

BACKGROUND: The effect that neonatal bacille Calmette-Guérin (BCG) vaccination has on tuberculin skin test (TST) results is not well evaluated in preschool children. METHODS: This was a retrospective cohort study of TST results in aboriginal children in Saskatchewan reserve communities. Records from the centralized provincial tuberculosis program were searched for aboriginal children aged 0 to 4 years during the time period 1991 to 1999. Only the first TST result reported as part of infant and preschool screening programs was considered. Children with active tuberculosis and those evaluated as part of a contact-tracing program were excluded. The BCG-vaccinated and unvaccinated groups were compared using wheal size cut points of 5 mm, 10 mm, and 15 mm. RESULTS: Data from 1,086 children with neonatal BCG vaccination and 1,867 unvaccinated children were analyzed. The rate of TST reactions was higher in vaccinated children at all ages, using a cut point of 5 mm. The rate of TST reactions was no different in vaccinated children >or= 1 year old when using a cut point of 15 mm. When using a cut point of 10 mm, the rate of TST reactions was higher at age 1 year but not different at age 4 years in the vaccinated children. CONCLUSION: The rate of TST reactions in preschool aboriginal children living on a reserve who have received neonatal BCG vaccination is affected by the cut point and age. The BCG vaccination status and age should therefore be considered when interpreting TST reactivity in the clinical assessment of aboriginal children participating in a tuberculosis control program.     

Clinical utility of the QuantiFERON TB-2G test for elderly patients with active tuberculosis

OBJECTIVE: To evaluate the response to the QuantiFERON-TB-2 Gold (QFT-2G) test (Cellestis Ltd; Carnegie, VIC, Australia) in elderly patients with active tuberculosis (TB) to determine whether the QFT-2G test might be a feasible method for diagnosing TB infection in this group of patients. METHODS: The subjects were 30 elderly patients with active TB and 100 younger patients with active TB. The QFT-2G test results were analyzed in relation to combined and separate responses to early secretory antigenic target 6-kD (ESAT-6) protein and culture filtrate protein 10 (CFP-10) antigens. RESULTS: Of the 30 elderly patients with active TB, 27% had a positive tuberculin skin test (TST) result and 77% had a positive QFT-2G test result. Of the 100 younger patients with active TB, 70% had a positive TST result and 87% had a positive QFT-2G test result. Although there was no significant difference between the two patient groups in the positive rate for the QFT-2G test results (p = 0.185), there was a significant difference in the rates of positive TST results between the elderly and younger patients (p = 0.012). The positive test result rate for both ESAT-6 and CFP-10 antigens in the elderly patients (17%) was significantly lower than that in younger patients (37%; p = 0.038). There was an indeterminate result for the QFT-2G test in five elderly patients, and this might have been related to the presence of lymphocytopenia due to underlying disease. A negative result on the QFT-2G test was detected in two elderly patients, and this might have been related to the severity of the active TB. CONCLUSION: We confirmed that the QFT-2G test might be a more useful method of diagnosing TB infection than the TST for elderly patients if peripheral lymphocyte counts have been preserved.     

Diagnosis and treatment of tuberculous pleural effusion in 2006

Tuberculous (TB) pleural effusion occurs in approximately 5% of patients with Mycobacterium tuberculosis infection. The HIV pandemic has been associated with a doubling of the incidence of extrapulmonary TB, which has resulted in increased recognition of TB pleural effusions even in developed nations. Recent studies have provided insights into the immunopathogenesis of pleural TB, including memory T-cell homing and chemokine activation. The definitive diagnosis of TB pleural effusions depends on the demonstration of acid-fast bacilli in the sputum, pleural fluid, or pleural biopsy specimens. The diagnosis can be established in a majority of patients from the clinical features, pleural fluid examination, including cytology, biochemistry, and bacteriology, and pleural biopsy. Measurement of adenosine deaminase and interferon-gamma in the pleural fluid and polymerase chain reaction for M tuberculosis has gained wide acceptance in the diagnosis of TB pleural effusions. Although promising, these tests require further evaluation before their routine use can be recommended. The treatment of TB pleural effusions in patients with HIV/AIDS is essentially similar to that in HIV-negative patients. At present, evidence regarding the use of corticosteroids in the treatment of TB pleural effusion is not clear-cut.     

Hepatitis C virus infection and hepatotoxicity during antituberculosis chemotherapy

BACKGROUND: The risk of drug-induced hepatotoxicity (DIH) during treatment for tuberculosis (TB) in patients who are seropositive for the hepatitis C virus (HCV) is not clear. We evaluated whether HCV-seropositive patients are at a higher risk of DIH than control subjects during treatment for TB with standard short-course regimens. METHODS: Fifty-four HCV-seropositive patients with newly diagnosed active TB who were treated with isoniazid, rifampin, ethambutol, and/or pyrazinamide were included in the study population. Ninety-seven HCV-seronegative patients were selected as control subjects. RESULTS: Forty HCV-seropositive patients (74%) and 82 control subjects (85%) received an initial treatment regimen that included pyrazinamide. Twenty-two HCV-seropositive patients (41%) and 19 control subjects (20%) exhibited elevated liver enzyme levels during TB treatment, including transient elevation of transaminase. DIH, defined as a liver transaminase level >/= 120 IU/L, occurred more frequently in HCV-seropositive patients (7 of 54 patients, 13%) than in control subjects (4 of 97 patients, 4%). Isoniazid and rifampin were reintroduced after the liver transaminase level returned to baseline in five HCV-seropositive patients exhibiting DIH, and all these retrials proved to be successful. CONCLUSIONS: These findings suggest that treatment for TB in HCV-seropositive patients could be pursued in the usual manner, using standard short-course regimens, with the condition that monthly liver function tests are carefully performed.     

Pleural tuberculosis in the United States: incidence and drug resistance

BACKGROUND: Pleural tuberculosis (TB) should be considered in any patient with a lymphocytic pleural effusion. The diagnostic approach is under debate. Knowledge of pleural TB epidemiology would be beneficial. To help clarify pleural TB epidemiology, we analyzed US national TB surveillance data for 1993 to 2003. METHODS: We compared pleural TB to pulmonary TB (where each was reported as the major site of TB disease, and no additional sites of disease were reported). Applicable statistical tests were performed; p < 0.05 was considered to be significant. RESULTS: From 1993 through 2003, 7,549 cases of pleural TB and 156,779 cases of pulmonary TB were reported (in 2003: pleural TB, 536 cases; pulmonary TB, 10,551 cases). The annual proportion of pleural TB was relatively stable (median rate, 3.6%; range, 3.3 to 4.0%) compared to that for pulmonary TB, which steadily decreased (average annual decrease, 0.9%; p < 0.01). Pleural TB occurred significantly more often than pulmonary TB among persons >/= 65 years old (30.4% vs 23.3%, respectively; p < 0.01), and it occurred significantly less often among children < 15 years old (1.8% vs 6.1%, respectively; p < 0.01) and persons 45 to 64 years old (22.9% vs 27.9%, respectively; p < 0.01). Pleural TB patients (63.4%) were born slightly more often in the United States than were pulmonary TB patients (60.9%; p < 0.01). Drug-resistance patterns of pleural TB broadly reflected those of pulmonary TB. However, isolates from pleural TB patients were less often resistant to at least isoniazid (6.0% vs 7.8%, respectively; p < 0.01) and to at least one first-line TB drug (9.9% vs 11.9%, respectively; p < 0.01) compared with pulmonary TB patients. CONCLUSIONS: Knowledge of pleural TB demographic, clinical, and drug-resistance patterns may assist clinicians in making diagnostic and therapeutic decisions.     

Pulmonary impairment after tuberculosis

BACKGROUND: Pulmonary impairment subsequent to a cure of pulmonary tuberculosis has been described only in selected populations. METHODS: We compared pulmonary function in a case-control study of 107 prospectively identified patients with pulmonary tuberculosis who had completed at least 20 weeks of therapy and 210 patients with latent tuberculosis infection (LTBI). RESULTS: Both groups had similar risk factors for pulmonary impairment. Impairment was present in 59% of tuberculosis subjects and 20% of LTBI control subjects. FVC, FEV1, FEV1/FVC ratio, and the midexpiratory phase of forced expiratory flow were significantly lower in the treated pulmonary tuberculosis patients than in the comparison group. Ten patients with a history of pulmonary tuberculosis (9.4%) had less than half of their expected vital capacity vs one patient (0.53%) in the LTBI group. Another 42 patients (39%) with tuberculosis had between 20% and 50% of the expected vital capacity vs 36 patients with LTBI (17%). After adjusting for risk, survivors of tuberculosis were 5.4 times more likely to have abnormal pulmonary function test results than were LTBI patients (p > 0.001; 95% confidence interval, 2.98 to 9.68). Birth in the United States (odds ratio [OR], 2.64; p = 0.003) and age (OR, 1.03; p = 0.005) increased the odds of impairment. Pulmonary impairment was more common in cigarette smokers; however, after adjusting for demographic and other risk factors, the difference did not reach statistical significance (p = 0.074). CONCLUSIONS: These findings indicate that pulmonary impairment after tuberculosis is associated with disability worldwide and support more aggressive case prevention strategies and posttreatment evaluation. For many persons with tuberculosis, a microbiological cure is the beginning not the end of their illness.     

Discrepant results between pyrazinamide susceptibility testing by the reference BACTEC 460TB method and pncA DNA sequencing in patients infected with multidrug-resistant W-Beijing Mycobacterium tuberculosis strains

BACKGROUND: Mycobacterium tuberculosis strains belonging to the W-Beijing family have received broad clinical and public health attention because of their rapid worldwide spread and their frequent association with outbreaks, multidrug resistance, and treatment failures and relapses. METHODS: The present study examined a large number of multidrug-resistant strain-W isolates (isolates of 29 patients) by susceptibility testing for pyrazinamide (PZA) using the reference BACTEC 460TB method (Becton Dickinson Diagnostic Instrument Systems; Sparks, MD) and also by DNA sequencing of the pncA gene. RESULTS: We found that despite of the presence of a strain W-specific Thr47Ala in the pncA gene, all strains showed susceptibility to PZA in the reference BACTEC 460TB system due to their higher minimum inhibitory concentrations (relative to BACTEC 460TB PZA-susceptible strains). CONCLUSIONS: Our results suggest that the current radiometric reference method cannot reproducibly detect PZA resistance in patients infected with W-Beijing strains. Therefore, PZA susceptibility testing should instead be based on analysis of the pncA gene for resistance-associated mutations.     

The effects of flexible bronchoscopy on mechanical ventilation in a pediatric lung model

BACKGROUND: Flexible bronchoscopy performed through endotracheal tubes (ETTs) in children receiving mechanical ventilation can significantly impact ventilation, but the magnitude of this impact has not been established. We used a lung model to simulate mechanical ventilation in a range of child sizes in order to determine how the insertion of pediatric flexible bronchoscopes into ETTs alters ventilatory parameters, especially tidal volume (Vt) and peak inspiratory pressure (PIP), in both healthy and diseased lungs. METHODS: We simulated five child sizes based on weight, and evaluated 22 bronchoscope/ETT combinations, first in pressure control (PC) ventilation mode and then in volume control (VC) ventilation mode. The combinations ranged from the 2.2-mm (bronchoscope outer diameter)/3.0-mm (ETT inner diameter) to 5.0-mm bronchoscope/8.0-mm ETT. The primary outcome measures were decrease in Vt after bronchoscope insertion during PC ventilation and increase in PIP during VC ventilation. RESULTS: In the PC ventilator mode, Vt decreased by > 50% with nine of the combinations, while during VC ventilation, PIP increased by >or= 20 cm H(2)O with seven combinations. The 2.2-mm bronchoscope/3.0-mm ETT, 2.8-mm bronchoscope/5.0-mm ETT, and 3.6-mm bronchoscope/5.0-mm ETT combinations severely impaired ventilation, while the 3.6-mm bronchoscope/4.5-mm ETT, 5.0-mm bronchoscope/6.5-mm ETT, and 5.0-mm bronchoscope/7.0-mm ETT combinations were incompatible with adequate ventilation. CONCLUSIONS: The insertion of bronchoscopes into ETTs can lead to clinically relevant decreases in Vt when in the PC ventilator mode and large increases in PIP during VC ventilation. The minimum bronchoscope/ETT diameter difference required to maintain adequate ventilation increases with child size.     

Survival of chronic hypercapnic COPD patients is predicted by smoking habits, comorbidity, and hypoxemia

STUDY OBJECTIVES: Chronic hypercapnia in patients with COPD has been associated with a poor prognosis. We hypothesized that, within this group of chronic hypercapnic COPD patients, factors that could mediate this hypercapnia, such as decreased maximum inspiratory mouth pressure (P(I(max))), decreased maximum expiratory mouth pressure (P(E(max))), and low hypercapnic ventilatory response (HCVR), could be related to survival. Other parameters, such as arterial blood gas values, airway obstruction (FEV1), body mass index (BMI), current smoking status, and the presence of comorbidity were studied as well. METHODS: A cohort of 47 chronic hypercapnic COPD patients recruited for short-term trials (1 to 3 weeks) in our institute was followed up for 3.8 years on average. Survival was analyzed using a Cox proportional hazards model. The risk factors considered were analyzed, optimally adjusted for age and gender. RESULTS: At the time of analysis 18 patients (10 male) were deceased. After adjusting for age and gender, P(I(max)), P(E(max)), and HCVR were not correlated with survival within this hypercapnic group. Current smoking (hazard ratio [HR], 7.0; 95% confidence interval [CI], 1.4 to 35.3) and the presence of comorbidity (HR, 5.5; 95% CI, 1.7 to 18.7) were associated with increased mortality. A higher Pa(O2) affected survival positively (HR, 0.6 per 5 mm Hg; 95% CI, 0.4 to 1.0). Pa(CO2) tended to be lower in survivors, but this did not reach statistical significance (HR, 2.0 per 5 mm Hg; 95% CI, 0.9 to 4.3). FEV1 and BMI were not significantly related with survival in hypercapnic COPD patients. CONCLUSION: In patients with chronic hypercapnia, only smoking status, the presence of comorbidity, and Pa(O2) level are significantly associated with survival. Airway obstruction, age, and BMI are known to be predictors of survival in COPD patients in general. However, these parameters do not seem to significantly affect survival once chronic hypercapnia has developed.     

Cytokine and chemokine expression profiles in response to Mycobacterium tuberculosis stimulation are altered in HIV-infected compared to HIV-uninfected subjects with active tuberculosis

Mycobacterium tuberculosis (Mtb) infects nearly 2 million people annually and is the most common cause of death in HIV-infected individuals. Tuberculosis (TB) diagnostics cater to HIV-uninfected individuals in non-endemic countries, are expensive, slow, and lack sensitivity for those most affected. Patterns of soluble immune markers from Mtb-stimulated immune cells are not well defined in HIV co-infection. We assessed immune differences between HIV-infected and HIV-uninfected individuals with active TB utilizing IFNγ-based QuantiFERON^®-TB Gold In-Tube (QFT) testing in Nairobi, Kenya. Excess QFT supernatants were used to measure cytokine and chemokine responses by a 17-plex bead array. Mtb/HIV co-infected participants were significantly less likely to be QFT+ (47.2% versus 84.2% in the HIV-uninfected group), and demonstrated lower expression of all cytokines except for IFNα2. Receiver operator characteristic analyses identified IL-1α as a potential marker of co-infection. Among HIV-infected individuals, CD4+ T cell count correlated weakly with the expression of several analytes. Co-expression analysis highlighted differences in immune profiles between the groups. These data suggest that there is a unique and detectable Mtb-specific immune response in co-infection. A better understanding of Mtb immunology can translate into much needed immunodiagnostics with enhanced sensitivity in HIV-infected individuals, facilitating their opportunity to obtain live-saving treatment.     

Portable exhaled nitric oxide measurement: Comparison with the "gold standard" technique

Background:The measurement of fractional exhaled nitric oxide (FENO) can assist in the diagnosis of asthma and may also act as a useful surrogate inflammatory marker on which to base treatment decisions in asthma management algorithms. Until recently, this technique was confined to research facilities and secondary care institutions. A portable nitric oxide analyzer (MINO; Aerocrine AB; Smidesvägen, Sweden) has been developed, but few data exist comparing this device with established, larger laboratory-based analyzers (NIOX; Aerocrine AB).Methods:A total of 101 asthmatic patients (64 treated with regular inhaled corticosteroids) and 50 healthy volunteers had simultaneous FENO measurements undertaken using NIOX and MINO devices.Results:In both asthmatic patients and healthy volunteers, there was a good correlation between the measurements obtained using each device (r= 0.94 and 0.96, respectively). Altman-Bland plots confirmed this agreement. Receiver operating characteristic curves discriminating asthmatic patients from healthy volunteers obtained using the NIOX and MINO showed a sensitivity of 83.2% and a specificity of 72% using cutoff values of 13 and 12.5 parts per billion, respectively.Conclusion:FENO values obtained using a portable analyzer correlate well with those obtained using an established laboratory analyzer and can be used to discriminate asthmatic from nonasthmatic patients. This may facilitate the measurement of asthmatic airway inflammation in primary care.     

Avaliação económica do dabigatrano na prevenção de acidentes vasculares cerebrais isquémicos em doentes com fibrilhação auricular não valvular

Introduction and ObjectivesTo estimate the cost-effectiveness and cost-utility of dabigatran in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Portugal.MethodologyA Markov model was used to simulate patients’ clinical course, estimating the occurrence of ischemic and hemorrhagic stroke, transient ischemic attack, systemic embolism, myocardial infarction, and intra- and extracranial hemorrhage. The clinical parameters are based on the results of the RE-LY trial, which compared dabigatran with warfarin, and on a meta-analysis that estimated the risk of each event in patients treated with aspirin or with no antithrombotic therapy.ResultsDabigatran provides an increase of 0.331 life years and 0.354 quality-adjusted life years for each patient. From a societal perspective, these clinical gains entail an additional expenditure of 2978 euros. Thus, the incremental cost is 9006 euros per life year gained and 8409 euros per quality-adjusted life year.ConclusionsThe results show that dabigatran reduces the number of events, especially the most severe such as ischemic and hemorrhagic stroke, as well as their long-term sequelae. The expense of dabigatran is partially offset by lower event-related costs and by the fact that INR monitoring is unnecessary. It can thus be concluded that the use of dabigatran in clinical practice in Portugal is cost-effective.