Interferon-gamma release assays: what is their role in the diagnosis of active tuberculosis?
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Adult↗
Biomedical subjects
Madhukar Pai
Publications and source records attributed to Madhukar Pai.
Accuracy and reliability of physical signs in the diagnosis of pleural effusion.
Although pleural effusion is a common disorder among patients presenting with respiratory symptoms, there is limited evidence on the accuracy and reliability of symptoms and signs for the diagnosis of pleural effusion. In our study, conducted at a rural hospital in India, two physicians, blind to history and chest radiograph findings, and to each other's results, independently evaluated 278 patients (196 men), aged 12 and older, admitted with respiratory symptoms. We did a blind and independent comparison of physical signs (asymmetric chest expansion, vocal fremitus, percussion note, breath sounds, crackles, vocal resonance and auscultatory percussion) with the reference standard (chest radiograph). We measured diagnostic accuracy by computing sensitivity, specificity, and likelihood ratios (LRs), and inter-observer reliability by using kappa (kappa) statistic. We performed multivariate analysis to identify the clinical signs that independently predict pleural effusion. The prevalence of pleural effusion was 21% (57/278). The LRs of positive signs ranged from 1.48 to 8.14 and their 95% confidence intervals (CIs) excluded 1. Except for pleural rub, the LRs for negative signs ranged between 0.13 and 0.71. The interobserver agreement was excellent for chest expansion, vocal fremitus, percussion and breath sounds (kappa 0.84-0.89) and good for vocal resonance, crackles and auscultatory percussion (kappa 0.68-0.78). The independent predictors of pleural effusion were asymmetric chest expansion (odds ratio [OR] 5.22, 95% CI 2.06-13.23), and dull percussion note (OR 12.80, 95% CI 4.23-38.70). For the final multivariate model, the area under receiver operating characteristic curve (ROC curve) was 0.88. In conclusion, our data suggest that physical signs may be helpful to rule out but not rule in pleural effusion.
Adolescent↗
Comparison of a whole blood interferon-gamma assay with tuberculin skin testing for the detection of tuberculosis infection in hospitalized children in rural India.
OBJECTIVE: In vitro interferon-gamma (IFN-gamma) assays have emerged as novel alternatives to the tuberculin skin test (TST) for the diagnosis of latent tuberculosis (TB) infection. These assays have been evaluated in low incidence countries, mainly in adults, and have been shown to be more specific than TST. Because few studies have been done in high incidence countries, and because paediatric data are limited, we compared a whole-blood IFN-gamma assay with TST among hospitalized Indian children. METHODS: Between July 2004 and June 2005, a total of 105 consecutively admitted children (median age 6 years; 82% had BCG scars) in whom TB was suspected or had history of contact with an index case were recruited at a rural hospital in India. All children underwent TST, and the QuantiFERON-TB-Gold In Tube (QFT) assay. RESULTS: The overall prevalence of TB infection was similar with both tests. With a TST cut-off point of > or =10mm, 10 of 105 (9.5%; 95% CI 3.8, 15.2) children were TST positive. With a cut-off point of IFN-gamma> or =0.35IU/ml, 11 of 105 (10.5%; 95% CI 4.5, 16.4) were QFT positive. The concordance between TST and QFT was substantial (agreement 95.2%; kappa [kappa] 0.73; 95% CI for kappa 0.53, 0.92). Agreement between TST and QFT results was 100% (kappa 1.0) in BCG scar-negative children as compared to 94% (kappa 0.63) in scar-positive children. BCG was not associated with the results of either TST or QFT (P>0.05 for both tests). The number of children with bacteriologically confirmed active TB was too small to permit the estimation of sensitivity of the tests. CONCLUSIONS: In a rural, predominantly BCG-vaccinated paediatric population in India, the TST and QFT assay produced comparable results. BCG vaccination did not significantly affect either TST or QFT results. Larger studies are needed to compare the sensitivity of the IFN-gamma assay with that of the TST in children with bacteriologically and/or clinically confirmed TB.
Child↗
Persistently elevated T cell interferon-gamma responses after treatment for latent tuberculosis infection among health care workers in India: a preliminary report.
BACKGROUND: T cell-based interferon-gamma (IFN-gamma) release assays (IGRAs) are novel tests for latent tuberculosis infection (LTBI). It has been suggested that T cell responses may be correlated with bacterial burden and, therefore, IGRAs may have a role in monitoring treatment response. We investigated IFN-gamma responses to specific TB antigens among Indian health care workers (HCWs) before, and after LTBI preventive therapy. METHODS: In 2004, we established a cohort of HCWs who underwent tuberculin skin testing (TST) and a whole-blood IGRA (QuantiFERON-TB-Gold In-Tube [QFT-G], Cellestis Ltd, Victoria, Australia) at a rural hospital in India. HCWs positive by either test were offered 6 months of isoniazid (INH) preventive therapy. Among the HCWs who underwent therapy, we prospectively followed-up 10 nursing students who were positive by both tests at baseline. The QFT-G assay was repeated 4 and 10 months after INH treatment completion (i.e. approximately 12 months and 18 months after the initial testing). IFN-gamma responses to ESAT-6, CFP-10 and TB7.7 peptides were measured using ELISA, and IFN-gamma >/=0.35 IU/mL was used to define a positive QFT-G test result. RESULTS: All participants (N = 10) reported direct contact with smear-positive TB patients at baseline, during and after LTBI treatment. All participants except one started treatment with high baseline IFN-gamma responses (median 10.0 IU/mL). The second QFT-G was positive in 9 of 10 participants, but IFN-gamma responses had declined (median 5.0 IU/mL); however, this difference was not significant (P = 0.10). The third QFT-G assay continued to be positive in 9 of 10 participants, with persistently elevated IFN-gamma responses (median 7.9 IU/mL; P = 0.32 for difference against baseline average). CONCLUSION: In an environment with ongoing, intensive nosocomial exposure, HCWs had strong IFN-gamma responses at baseline, and continued to have persistently elevated responses, despite LTBI treatment. It is plausible that persistence of infection and/or re-infection might account for this phenomenon. Our preliminary findings need confirmation in larger studies in high transmission settings. Specifically, research is needed to study T cell kinetics during LTBI treatment, and determine the effect of recurrent exposures on host cellular immune responses.
Journal Article↗
Serial testing of health care workers for tuberculosis using interferon-gamma assay.
RATIONALE: Although interferon-gamma (IFN-gamma) assays are promising alternatives to the tuberculin skin test (TST), their serial testing performance is unknown. OBJECTIVE: To compare TST and IFN-gamma conversions and reversions in healthcare workers. METHODS: We prospectively followed-up 216 medical and nursing students in India who underwent baseline and repeat testing (after 18 mo) with TST and QuantiFERON-TB Gold In-Tube (QFT). TST conversions were defined as reactions greater than or equal to 10 mm, with increments of 6 or 10 mm over baseline. QFT conversions were defined as baseline IFN-gamma less than 0.35 and follow-up IFN-gamma greater than or equal to 0.35 or 0.70 IU/ml. QFT reversions were defined as baseline IFN-gamma greater than or equal to 0.35 and follow-up IFN-gamma less than 0.35 IU/ml. RESULTS: Of the 216 participants, 48 (22%) were TST-positive, and 38 (18%) were QFT-positive at baseline. Among 147 participants with concordant baseline negative results, TST conversions occurred in 14 (9.5%; 95% confidence interval [CI] = 5.3-15.5) using the 6 mm increment definition, and 6 (4.1%; 95% CI = 1.5-8.7) using the 10 mm increment definition. QFT conversions occurred in 17/147 participants (11.6%; 95% CI = 6.9-17.9) using the definition of IFN-gamma greater than or equal to 0.35 IU/ml, and 11/147 participants (7.5%; 95% CI = 3.8-13.0) using IFN-gamma greater than or equal to 0.70 IU/ml. Agreement between TST (10 mm increment) and QFT conversions (>or= 0.70 IU/ml) was 96% (kappa = 0.70). QFT reversions occurred in 2/28 participants (7%) with baseline concordant positive results, as compared with 7/10 participants (70%) with baseline discordant results (p < 0.001). CONCLUSIONS: IFN-gamma assay shows promise for serial testing, but repeat results need to be interpreted carefully. To meaningfully interpret serial results, the optimal thresholds to distinguish new infections from nonspecific variations must be determined.
Adult↗
Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review.
Most of the world's tuberculosis cases occur in low-income and middle-income countries, where sputum microscopy with a conventional light microscope is the primary method for diagnosing pulmonary tuberculosis. A major shortcoming of conventional microscopy is its relatively low sensitivity compared with culture, especially in patients co-infected with HIV. In high-income countries, fluorescence microscopy rather than conventional microscopy is the standard diagnostic method. Fluorescence microscopy is credited with increased sensitivity and lower work effort, but there is concern that specificity may be lower. We did a systematic review to summarise the accuracy of fluorescence microscopy compared with conventional microscopy. By searching many databases and contacting experts, we identified 45 relevant studies. Sensitivity, specificity, and incremental yield were the outcomes of interest. The results suggest that, overall, fluorescence microscopy is more sensitive than conventional microscopy, and has similar specificity. There is insufficient evidence to determine the value of fluorescence microscopy in HIV-infected individuals. The results of this review provide a point of reference, quantifying the potential benefit of fluorescence microscopy, with which the increased cost and technical complexity of the method can be compared to determine the possible value of the method under programme conditions.
Cytodiagnosis↗
Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review.
In low-income and middle-income countries, direct (unconcentrated) sputum smear microscopy is the primary method for diagnosing pulmonary tuberculosis. The method is fast, inexpensive, and specific for Mycobacterium tuberculosis in high incidence areas. The main limitations of direct microscopy are its relatively low sensitivity, especially in individuals co-infected with HIV, and variable quality of the test in programme conditions. Thus, there is a need to identify methods to improve the sensitivity of microscopy. Physical and chemical sputum processing methods, including centrifugation, sedimentation, and bleach, have been studied and found to show promise. We did a systematic review to assess the ability of different processing methods to improve the sensitivity of microscopy. By searching many sources, we identified 83 studies. Overall, by comparison with direct smears, the results suggested that centrifugation with any of several chemical methods (including bleach) is more sensitive, that overnight sedimentation preceded by chemical processing is more sensitive, and that specificity is similar. There were insufficient data to determine the value of sputum processing methods in patients with HIV infection. Operational studies are needed to determine whether the increased sensitivity provided by processing methods is sufficient to offset their increased cost, complexity, and potential biohazards, and to examine their feasibility.
Bacteriological Techniques↗
International standards for tuberculosis care.
Part of the reason for failing to bring about a more rapid reduction in tuberculosis incidence worldwide is the lack of effective involvement of all practitioners-public and private-in the provision of high quality tuberculosis care. While health-care providers who are part of national tuberculosis programmes have been trained and are expected to have adopted proper diagnosis, treatment, and public-health practices, the same is not likely to be true for non-programme providers. Studies of the performance of the private sector conducted in several different parts of the world suggest that poor quality care is common. The basic principles of care for people with, or suspected of having, tuberculosis are the same worldwide: a diagnosis should be established promptly; standardised treatment regimens should be used with appropriate treatment support and supervision; response to treatment should be monitored; and essential public-health responsibilities must be carried out. Prompt and accurate diagnosis, and effective treatment are essential for good patient care and tuberculosis control. All providers who undertake evaluation and treatment of patients with tuberculosis must recognise that not only are they delivering care to an individual, but they are also assuming an important public-health function. The International Standards for Tuberculosis Care (ISTC) describe a widely endorsed level of care that all practitioners should seek to achieve in managing individuals who have, or are suspected of having, tuberculosis. The document is intended to engage all care providers in delivering high quality care for patients of all ages, including those with smear-positive, smear-negative, and extra-pulmonary tuberculosis, tuberculosis caused by drug-resistant Mycobacterium tuberculosis complex, and tuberculosis combined with HIV infection.
Antitubercular Agents↗
Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine for uncomplicated malaria: a systematic review.
OBJECTIVE: To compare the efficacies against uncomplicated falciparum malaria of chloroquine (CQ), amodiaquine (AQ), sulfadoxine-pyrimethamine (SP) and combinations of these inexpensive drugs. METHODS: We searched Medline, Embase, Cochrane CENTRAL Register of Controlled Trials, BIOSIS, Web of Science, African Index Medicus, DARE, Digital Dissertations and Current Controlled Trials for randomised or quasi-randomised controlled trials conducted between 1991 and June 2004 regardless of language and geography. We also contacted malaria experts, searched reference lists, and contacted individual authors for unreported study characteristics and additional data. Unpublished data were sought and included in the analyses. RESULTS: Thirteen randomised trials (n = 4248) were identified and the summary relative risks of treatment failure at 28 days were calculated. There was marginal benefit in adding CQ to SP, compared with SP monotherapy (RR = 0.74, 95% CI 0.54-1.02). Combining AQ with SP was associated with a significantly lower risk of treatment failure than SP monotherapy (RR = 0.35, 95% CI 0.15-0.82) and AQ monotherapy (RR = 0.59, 95% CI 0.42-0.83). AQ plus SP was associated with a significantly lower risk of treatment failure than CQ plus SP (RR = 0.42, 95% CI 0.25-0.72). Serious adverse events were rare and did not increase with combination therapy. CONCLUSION: Amodiaquine plus SP remains an efficacious, affordable and safe option for treating malaria in certain settings.
Amodiaquine↗
Tuberculosis among health-care workers in low- and middle-income countries: a systematic review.
BACKGROUND: The risk of transmission of Mycobacterium tuberculosis from patients to health-care workers (HCWs) is a neglected problem in many low- and middle-income countries (LMICs). Most health-care facilities in these countries lack resources to prevent nosocomial transmission of tuberculosis (TB). METHODS AND FINDINGS: We conducted a systematic review to summarize the evidence on the incidence and prevalence of latent TB infection (LTBI) and disease among HCWs in LMICs, and to evaluate the impact of various preventive strategies that have been attempted. To identify relevant studies, we searched electronic databases and journals, and contacted experts in the field. We identified 42 articles, consisting of 51 studies, and extracted data on incidence, prevalence, and risk factors for LTBI and disease among HCWs. The prevalence of LTBI among HCWs was, on average, 54% (range 33% to 79%). Estimates of the annual risk of LTBI ranged from 0.5% to 14.3%, and the annual incidence of TB disease in HCWs ranged from 69 to 5,780 per 100,000. The attributable risk for TB disease in HCWs, compared to the risk in the general population, ranged from 25 to 5,361 per 100,000 per year. A higher risk of acquiring TB disease was associated with certain work locations (inpatient TB facility, laboratory, internal medicine, and emergency facilities) and occupational categories (radiology technicians, patient attendants, nurses, ward attendants, paramedics, and clinical officers). CONCLUSIONS: In summary, our review demonstrates that TB is a significant occupational problem among HCWs in LMICs. Available evidence reinforces the need to design and implement simple, effective, and affordable TB infection-control programs in health-care facilities in these countries.
Allied Health Personnel↗
Advances in the diagnosis and treatment of tuberculosis.
Although truly major advances that would revolutionize tuberculosis (TB) diagnosis and treatment have not been realized, we are beginning to see the innovations that have been prompted by the recognition of the economic potential of the market for new diagnostic tests and treatments for TB and considerably increased public and private funding. Despite the enormous global burden of TB and the overall low rates of case detection worldwide, conventional approaches to diagnosis have, until recently, relied on tests that have major limitations. In this review of advances in diagnosis, we focus on strengths and limitations of newer tests that are available for the diagnosis of latent and active tuberculosis and rapid detection of drug resistance, specifically, tests that measure release of IFN-gamma in response to stimulation by Mycobacterium tuberculosis antigens, nucleic acid amplification for identification of M. tuberculosis complex, and rapid tests for detecting drug resistance. Standard regimens for treating TB have not changed for more than 30 yr and still require a minimum of 6 mo to have a high likelihood of a lasting cure. In this article, we focus on important changes in the philosophy of treatment, emphasizing the responsibility of the provider to assure successful completion of treatment, and on the roles of existing anti-TB agents and newer drugs such as rifabutin, rifapentine, and fluoroquinolones.
Antitubercular Agents↗
New tools and emerging technologies for the diagnosis of tuberculosis: part I. Latent tuberculosis.
Nearly a third of the world's population is estimated to be infected with Mycobacterium tuberculosis. This enormous pool of latently infected individuals poses a major hurdle for global tuberculosis (TB) control. Currently, diagnosis of latent TB infection (LTBI) relies on the tuberculin skin test (TST), a century-old test with known limitations. In this review, the first of a two-part series on new tools for TB diagnosis, recent advances in the diagnosis of LTBI are described. The biggest advance in recent years has been the development of in vitro T-cell-based interferon-gamma release assays (IGRAs) that use antigens more specific to M. tuberculosis than the purified protein derivative used in the TST. Available research evidence on IGRAs suggests they have higher specificity than TST, better correlation with surrogate markers of exposure to M. tuberculosis in low-incidence settings, and less cross-reactivity due to BCG vaccination than the TST. IGRAs also appear to be at least as sensitive as the purified protein derivative-based TST for active TB. In the absence of a gold standard for LTBI, sensitivity and specificity for LTBI are not well defined. Besides high specificity, other potential advantages of IGRAs include logistical convenience, avoidance of poorly reproducible measurements, such as skin induration, need for fewer patient visits and the ability to perform serial testing without inducing the boosting phenomenon. Overall, due to its high specificity, IGRAs may be useful in low-endemic, high-income settings where cross-reactivity due to BCG might adversely impact the utility of TST. However, despite the growing evidence supporting the use of IGRAs, several unresolved and unexplained issues remain. The review concludes by highlighting areas where evidence is lacking, and provides an agenda for future research. Active TB and drug resistance are discussed in Part II; 423-432 of this issue.
Antigens, Bacterial↗
New tools and emerging technologies for the diagnosis of tuberculosis: part II. Active tuberculosis and drug resistance.
Tuberculosis (TB) is one of the world's most important infectious causes of morbidity and mortality among adults. Between 8 and 9 million develop TB disease, and approximately 2 million die from TB each year. Despite this enormous global burden, case detection rates are low, posing major hurdles for TB control. Conventional TB diagnosis continues to rely on smear microscopy, culture and chest radiography. These tests have known limitations. Conventional tests for detection of drug resistance are slow, tedious and difficult to perform in field conditions. This second half of a two-part review series on new tools for TB diagnosis describes recent advances and emerging technologies in the diagnosis of active disease, and detection of drug resistance. For diagnosis, new tools include newer versions of nucleic acid amplification tests, immune-based assays, skin patch test and rapid culture systems. For drug resistance, new tools include line-probe assays, bacteriophage-based assays, molecular beacons and microscopic observation drug susceptibility assay. Although the ideal test for TB is still not in sight, substantial progress has been made in the past decade. With the resurgence of interest in the development of new tools for TB control, it is likely that the next decade will see greater progress and tangible benefits. However, the challenge will be to ensure that new tools undergo rigorous evaluations in field conditions, and also to make sure that benefits of promising new tools actually reach the populations in developing countries that need them most. Latent TB is discussed in Part I; 413-422 of this issue.
Antigens, Bacterial↗
Tuberculosis diagnostics trials: do they lack methodological rigor?
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Clinical Trials as Topic↗
Nosocomial tuberculosis in India.
Most high-income countries implement tuberculosis (TB) infection control programs to reduce the risk for nosocomial transmission. However, such control programs are not routinely implemented in India, the country that accounts for the largest number of TB cases in the world. Despite the high prevalence of TB in India and the expected high probability of nosocomial transmission, little is known about nosocomial and occupational TB there. The few available studies suggest that nosocomial TB may be a problem. We review the available data on this topic, describe factors that may facilitate nosocomial transmission in Indian healthcare settings, and consider the feasibility and applicability of various recommended infection control interventions in these settings. Finally, we outline the critical information needed to effectively address the problem of nosocomial transmission of TB in India.
Adult↗
Discordance between tuberculin skin test and interferon-gamma assays.
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Biomarkers↗
In-house nucleic acid amplification tests for the detection of Mycobacterium tuberculosis in sputum specimens: meta-analysis and meta-regression.
BACKGROUND: More than 200 studies related to nucleic acid amplification (NAA) tests to detect Mycobacterium tuberculosis directly from clinical specimens have appeared in the world literature since this technology was first introduced. NAA tests come as either commercial kits or as tests designed by the reporting investigators themselves (in-house tests). In-house tests vary widely in their accuracy, and factors that contribute to heterogeneity in test accuracy are not well characterized. Here, we used meta-analytical methods, including meta-regression, to identify factors related to study design and assay protocols that affect test accuracy in order to identify those factors associated with high estimates of accuracy. RESULTS: By searching multiple databases and sources, we identified 2520 potentially relevant citations, and analyzed 84 separate studies from 65 publications that dealt with in-house NAA tests to detect M. tuberculosis in sputum samples. Sources of heterogeneity in test accuracy estimates were determined by subgroup and meta-regression analyses. Among 84 studies analyzed, the sensitivity and specificity estimates varied widely; sensitivity varied from 9.4% to 100%, and specificity estimates ranged from 5.6% to 100%. In the meta-regression analysis, the use of IS6110 as a target, and the use of nested PCR methods appeared to be significantly associated with higher diagnostic accuracy. CONCLUSION: Estimates of accuracy of in-house NAA tests for tuberculosis are highly heterogeneous. The use of IS6110 as an amplification target, and the use of nested PCR methods appeared to be associated with higher diagnostic accuracy. However, the substantial heterogeneity in both sensitivity and specificity of the in-house NAA tests rendered clinically useful estimates of test accuracy difficult. Future development of NAA-based tests to detect M. tuberculosis from sputum specimens should take into consideration these findings in improving accuracy of in-house NAA tests.
Gene Amplification↗
Interferon-gamma assays for tuberculosis: is anergy the Achilles' heel?
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Humans↗