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Journal of Clinical Microbiology Apr 2021Unstimulated interferon gamma may be a useful pleural fluid biomarker in the diagnosis of tuberculous pleural effusion (TPE). However, the exact threshold of pleural... (Meta-Analysis)
Meta-Analysis Review
Unstimulated interferon gamma may be a useful pleural fluid biomarker in the diagnosis of tuberculous pleural effusion (TPE). However, the exact threshold of pleural fluid interferon gamma and its accuracy during routine clinical decision-making is not clear. We assessed the performance of pleural fluid interferon gamma in diagnosing TPE and tried to identify a useful assay threshold. We queried the PubMed and Embase databases for publications indexed until May 2020 that provided both sensitivity and specificity data on unstimulated pleural fluid interferon gamma for diagnosis of TPE. A bivariate random effects model was employed to compute summary estimates for diagnostic accuracy parameters, both overall as well as at threshold ranges of <2, 2 to 5, and >5 IU/ml. We retrieved 2,048 citations, of which 67 publications (7,153 patients) were assessed in our review. The summary estimates for sensitivity, specificity, and diagnostic odds ratio were 0.93 (95% confidence interval [CI], 0.91 to 0.95), 0.96 (95% CI, 0.94 to 0.97), and 310.72 (95% CI, 185.24 to 521.18), respectively. Increasing interferon gamma thresholds did not translate into any substantial change in diagnostic performance; however, eight studies using thresholds of >5 IU/ml showed poorer diagnostic accuracy estimates than other studies with lower thresholds. None of the prespecified subgroup variables significantly influenced relative diagnostic odds ratios in a multivariate meta-regression model. All publications demonstrated a high risk of bias. Unstimulated pleural fluid interferon gamma level provides excellent accuracy for diagnosing TPE and has the potential of becoming a first-line test for this purpose.
Topics: Adenosine Deaminase; Biomarkers; Exudates and Transudates; Humans; Interferon-gamma; Pleural Effusion; Sensitivity and Specificity; Tuberculosis, Pleural
PubMed: 33208475
DOI: 10.1128/JCM.02112-20 -
Annals of Translational Medicine Oct 2019Several studies have investigated the diagnostic accuracy of serum lactate dehydrogenase (LDH) to pleural fluid adenosine deaminase ratio (cancer ratio, CR) for...
BACKGROUND
Several studies have investigated the diagnostic accuracy of serum lactate dehydrogenase (LDH) to pleural fluid adenosine deaminase ratio (cancer ratio, CR) for malignant pleural effusion (MPE), but the results were various. Therefore, we performed this systematic review and meta-analysis to ascertain the diagnostic accuracy of CR for MPE.
METHODS
The PubMed and EMBASE databases were searched up to 7 June, 2019 to identify publications concerning diagnostic accuracy of CR for MPE. The sensitivities and specificities of CR in included studies were pooled with a bivariate model. A summary receiver operating characteristic (sROC) curve was used to estimate the global diagnostic accuracy of CR. Quality of the included studies was assessed with the revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2).
RESULTS
Finally, five studies with 596 MPE patients and 863 benign pleural effusion (BPE) patients were included in this systematic review and meta-analysis. The pooled sensitivity and specificity of CR were 0.97 (95% CI: 0.92-0.99) and 0.89 (0.69-0.97), respectively. The area under sROC curve was 0.98 (95% CI: 0.97-0.99). The major design weaknesses of the included studies were patients selection and partial verification bias.
CONCLUSIONS
CR has high diagnostic accuracy for MPE. Considering the design weaknesses of available studies, further studies with rigorous design are needed to further validate the findings of this meta-analysis.
PubMed: 31807535
DOI: 10.21037/atm.2019.09.85 -
Pediatric Research Mar 2020To develop a set of clinical criteria that identifies patients with a potential autoinflammatory IFNopathy. (Comparative Study)
Comparative Study
OBJECTIVE
To develop a set of clinical criteria that identifies patients with a potential autoinflammatory IFNopathy.
METHODS
Based on a literature review, a set of clinical criteria identifying genetically confirmed monogenic IFNopathies was selected. For validation, the clinical score was assessed in healthy controls (HCs) and 18 disease controls, including 2 known autoimmune IFNopathies, juvenile systemic lupus erythematosus (JSLE, n = 4) and dermatomyositis (JDM, n = 4); adenosine deaminase 2 deficiency (DADA2, n = 4); and oligoarticular juvenile idiopathic arthritis (oJIA, n = 6). We assessed an IFN score (IRG-S) in whole blood by NanoString using a previously published 28-gene-IRG-S and a reduced 6-gene-IRG-S.
RESULTS
The 12 patients with a possible IFNopathy had higher clinical scores (3-5) than the patients with sJLE, JDM, DADA2, and oJIA and in HCs. Both the 28-IRG-S and 6-IRG-S were significantly higher in the autoinflammatory IFNopathy patients compared to HCs and oJIA and DADA2 patients but not different from patients with JSLE and JDM. Subsequently, genetic analysis revealed mutations in genes previously reported in genes related to the IFN pathway in 9 of the 12 patients.
CONCLUSION
We developed a clinical score to identify patients with possible autoinflammatory IFNopathies. A clinical score was associated with a high IRG-S and may serve to identify patients with an autoinflammatory IFNopathy.
Topics: Age of Onset; Arthritis, Juvenile; Case-Control Studies; Child; Child, Preschool; Clinical Decision Rules; Clinical Decision-Making; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Infant; Interferon Type I; Lupus Erythematosus, Systemic; Male; Mutation; Phenotype; Predictive Value of Tests; Prognosis; Reproducibility of Results
PubMed: 31641281
DOI: 10.1038/s41390-019-0614-2 -
PloS One 2019Pleural fluid adenosine deaminase (ADA) is a useful diagnostic test for tuberculous pleural effusion (TPE), but its exact threshold and accuracy in clinical... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Pleural fluid adenosine deaminase (ADA) is a useful diagnostic test for tuberculous pleural effusion (TPE), but its exact threshold and accuracy in clinical decision-making is unclear. We aimed to assess diagnostic performance of ADA in TPE and to clarify its optimal diagnostic threshold.
METHODS
We searched PubMed, Embase, and Cochrane Library databases for articles indexed up to October 2018. We included English language studies that provided both sensitivity and specificity of ADA in TPE diagnosis. Summary estimates for sensitivity and specificity were obtained through bivariate random effects model, both overall and at prespecified threshold ranges of <36, 40±4, 45-65 and >65 IU/L.
RESULTS
We retrieved 2162 citations, and included 174 publications with 27009 patients. All studies showed high risk of bias. Summary sensitivity, specificity and diagnostic odds ratio estimates were 0.92 (95% CI 0.90-0.93), 0.90 (95% CI 0.88-0.91) and 97.42 (95% CI 74.90-126.72) respectively. 65 studies with ADA threshold of 40±4 IU/L showed summary sensitivity and specificity of 0.93 (95% CI 0.90-0.95) and 0.90 (95% CI 0.87-0.91) respectively. Four studies with ADA threshold >65 IU/L showed summary sensitivity and specificity of 0.86 (95% CI 0.61-0.96) and 0.94 (95% CI 0.80-0.99) respectively.
CONCLUSION
ADA levels in pleural fluid show good diagnostic accuracy in diagnosis of TPE; however, all included studies showed high risk of bias. It was not possible to derive any firm inference on relative clinical utility of different diagnostic thresholds.
Topics: Adenosine Deaminase; Animals; Female; Humans; Male; Pleural Effusion; Tuberculosis, Pleural
PubMed: 30913213
DOI: 10.1371/journal.pone.0213728 -
Sports Medicine (Auckland, N.Z.) May 2015'Natural selection' has been shown to have enriched the genomes of high-altitude native populations with genetic variants of advantage in this hostile hypoxic... (Review)
Review
BACKGROUND AND OBJECTIVE
'Natural selection' has been shown to have enriched the genomes of high-altitude native populations with genetic variants of advantage in this hostile hypoxic environment. In lowlanders who ascend to altitude, genetic factors may also contribute to the substantial interindividual variation in exercise performance noted at altitude. We performed a systematic literature review to identify genetic variants of possible influence on human hypoxic exercise performance, commenting on the strength of any identified associations.
CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW
All studies of the association of genetic factors with human hypoxic exercise performance, whether at sea level using 'nitrogen dilution of oxygen' (normobaric hypoxia), or at altitude or in low-pressure chambers (field or chamber hypobaric hypoxia, respectively) were sought for review.
SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES
Two electronic databases were searched (Ovid MEDLINE, Embase) up to 31 January 2014. We also searched the reference lists of relevant articles for eligible studies. All studies published in English were included, as were studies in any language for which the abstract was available in English.
DATA COLLECTION AND ANALYSIS
Studies were selected and data extracted independently by two reviewers. Differences regarding study inclusion were resolved through discussion. The quality of each study was assessed using a scoring system based on published guidelines for conducting and reporting genetic association studies.
RESULTS
A total of 11 studies met all inclusion criteria and were included in the review. Subject numbers ranged from 20 to 1,931 and consisted of healthy individuals in all cases. The maximum altitude of exposure ranged from 2,690 to 8,848 m. The exercise performance phenotypes assessed were mountaineering performance (n = 5), running performance (n = 2), and maximum oxygen consumption ([Formula: see text]O2max) (n = 4). In total, 13 genetic polymorphisms were studied, four of which were associated with hypoxic exercise performance. The adenosine monophosphate deaminase (AMPD1) C34T (rs17602729), beta2-adrenergic receptor (ADRB2) Gly16Arg single nucleotide polymorphism (SNP) (rs1042713), and androgen receptor CAG repeat polymorphisms were associated with altitude performance in one study, and the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) (rs4646994) polymorphism was associated with performance in three studies. The median score achieved in the study quality analysis was 6 out of 10 for case-control studies, 8 out of 10 for cohort studies with a discrete outcome, 6 out of 9 for cohort studies with a continuous outcome, and 4.5 out of 8 for genetic admixture studies.
CONCLUSION
The small number of articles identified in the current review and the limited number of polymorphisms studied in total highlights that the influence of genetic factors on exercise performance in hypoxia has not been studied in depth, which precludes firm conclusions being drawn. Support for the association between the ACE-I allele and improved high-altitude performance was the strongest, with three studies identifying a relationship. Analysis of study quality highlights the need for future studies in this field to improve the conduct and reporting of genetic association studies.
Topics: AMP Deaminase; Actinin; Altitude Sickness; Athletic Performance; Exercise; Genetic Variation; Genotype; Humans; INDEL Mutation; Oxygen Consumption; Peptidyl-Dipeptidase A
PubMed: 25682119
DOI: 10.1007/s40279-015-0309-8 -
International Journal of Clinical and... 2014This systematic review and meta-analysis was performed to determine accuracy and usefulness of adenosine deaminase (ADA) in diagnosis of tuberculosis pleurisy. Medline,... (Review)
Review
This systematic review and meta-analysis was performed to determine accuracy and usefulness of adenosine deaminase (ADA) in diagnosis of tuberculosis pleurisy. Medline, Google scholar and Web of Science databases were searched to identify related studies until 2014. Two reviewers independently assessed quality of studies included according to standard Quality Assessment of Diagnosis Accuracy Studies (QUADAS) criteria. The sensitivity, specificity, diagnostic odds ratio and other parameters of ADA in diagnosis of tuberculosis pleurisy were analyzed with Meta-DiSC1.4 software, and pooled using the random effects model. Twelve studies including 865 tuberculosis pleurisy patients and 1379 non-tuberculosis pleurisy subjects were identified from 110 studies for this meta-analysis. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnosis odds ratio (DOR) of ADA in the diagnosis of tuberculosis pleurisy were 45.25 (95% CI 27.63-74.08), 0.86 (95% CI 0.84-0.88), 0.88 (95% CI 0.86-0.90), 6.32 (95% CI 4.83-8.26) and 0.15 (95% 0.11-0.22), respectively. The area under the summary receiver operating characteristic curve (SROC) was 0.9340. Our results demonstrate that the sensitivity and specificity of ADA are high in the diagnosis of tuberculosis pleurisy especially when ADA≥50 (U/L). Thus, ADA is a relatively sensitive and specific marker for tuberculosis pleurisy diagnosis. However, it is cautious to apply these results due to the heterogeneity in study design of these studies. Further studies are required to confirm the optimal cut-off value of ADA.
PubMed: 25419343
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Jan 2015Recently, there has been a renewed interest in the development of new drugs for the treatment of leishmaniasis. This has spurred the need for pharmacodynamic markers to... (Review)
Review
Recently, there has been a renewed interest in the development of new drugs for the treatment of leishmaniasis. This has spurred the need for pharmacodynamic markers to monitor and compare therapies specifically for visceral leishmaniasis, in which the primary recrudescence of parasites is a particularly long-term event that remains difficult to predict. We performed a systematic review of studies evaluating biomarkers in human patients with visceral, cutaneous, and post-kala-azar dermal leishmaniasis, which yielded a total of 170 studies in which 53 potential pharmacodynamic biomarkers were identified. In conclusion, the large majority of these biomarkers constituted universal indirect markers of activation and subsequent waning of cellular immunity and therefore lacked specificity. Macrophage-related markers demonstrate favorable sensitivity and times to normalcy, but more evidence is required to establish a link between these markers and clinical outcome. Most promising are the markers directly related to the parasite burden, but future effort should be focused on optimization of molecular or antigenic targets to increase the sensitivity of these markers. In general, future research should focus on the longitudinal evaluation of the pharmacodynamic biomarkers during treatment, with an emphasis on the correlation of studied biomarkers and clinical parameters.
Topics: Acute-Phase Proteins; Adenosine Deaminase; Antibodies, Protozoan; Antigens, Protozoan; Biomarkers; Cytokines; Humans; Immunity, Cellular; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Macrophages; Membrane Proteins; Treatment Outcome
PubMed: 25367913
DOI: 10.1128/AAC.04298-14 -
Clinical & Developmental Immunology 2012High HIV burden countries have experienced a high burden of pleural TB in HIV-infected patients. (Review)
Review
BACKGROUND
High HIV burden countries have experienced a high burden of pleural TB in HIV-infected patients.
OBJECTIVE
To review the epidemiology, immunopathogenesis, diagnosis, and treatment of pleural TB in HIV-infected patients.
METHODS
A literature search from 1950 to June 2011 in MEDLINE was conducted.
RESULTS
Two-hundred and ninety-nine studies were identified, of which 30 met the inclusion criteria. The immunopathogenesis as denoted by cells and cytokine profiles is distinctly different between HIV and HIV-uninfected pleural TB disease. Adenosine deaminase and interferon gamma are good markers of pleural TB disease even in HIV-infected patients. HIV-uninfected TB suspects with pleural effusions commonly have a low yield of TB organisms however the evidence suggests that in dually infected patients smear and cultures have a higher yield. The Gene Xpert MTB/RIF assay has significant potential to improve the diagnosis of pleural TB in HIV-positive patients.
CONCLUSIONS
Pleural TB in HIV-infected patients has a different immunopathogenesis than HIV-uninfected pleural TB and these findings in part support the differences noted in this systematic review. Research should focus on developing an interferon gamma-based point of care diagnostic test and expansion of the role of Gene Xpert in the diagnosis of pleural TB.
Topics: Adenosine Deaminase; Anti-HIV Agents; Antitubercular Agents; Bacterial Load; Biomarkers; CD4 Lymphocyte Count; Coinfection; HIV Infections; HIV-1; Humans; Interferon-gamma; Mycobacterium tuberculosis; Tuberculosis, Pleural; Viral Load
PubMed: 22474483
DOI: 10.1155/2012/842045 -
Respiratory Medicine May 2008Conventional tests are not always helpful in making a diagnosis of tuberculous pleurisy. Many studies have investigated the usefulness of adenosine deaminase (ADA) in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Conventional tests are not always helpful in making a diagnosis of tuberculous pleurisy. Many studies have investigated the usefulness of adenosine deaminase (ADA) in pleural fluid for the early diagnosis of tuberculous pleurisy. We conducted a meta-analysis to determine the accuracy of ADA measurements in the diagnosis of tuberculous pleurisy.
METHODS
After a systematic review of English language studies, sensitivity, specificity, and other measures of accuracy of ADA concentration in the diagnosis of pleural effusion were pooled using random effects models. Summary receiver operating characteristic curves were used to summarize overall test performance.
RESULTS
Sixty-three studies met our inclusion criteria. The summary estimates for ADA in the diagnosis of tuberculous pleurisy in the studies included were sensitivity 0.92 (95% confidence interval 0.90-0.93), specificity 0.90 (95% confidence interval 0.89-0.91), positive likelihood ratio 9.03 (95% confidence interval 7.19-11.35), negative likelihood ratio 0.10 (95% confidence interval 0.07-0.14), and diagnostic odds ratio 110.08 (95% confidence interval 69.96-173.20).
CONCLUSIONS
ADA determination is a relative sensitive and specific test for the diagnosis of tuberculous pleurisy. Measurement of ADA in pleural effusion is thus likely to be a useful diagnostic tool for tuberculous pleurisy. The results of ADA assays should be interpreted in parallel with clinical findings and the results of conventional tests.
Topics: Adenosine Deaminase; Biomarkers; Clinical Enzyme Tests; Humans; Mycobacterium tuberculosis; Odds Ratio; Pleural Effusion; ROC Curve; Sensitivity and Specificity; Tuberculosis, Pleural
PubMed: 18222681
DOI: 10.1016/j.rmed.2007.12.007 -
Health Technology Assessment... Jan 2007To evaluate the effectiveness of available rapid diagnostic tests to identify tuberculosis (TB) infection. (Review)
Review
OBJECTIVES
To evaluate the effectiveness of available rapid diagnostic tests to identify tuberculosis (TB) infection.
DATA SOURCES
Electronic databases were searched from 1975 to August 2003 for tests for active TB and to March 2004 for tests for latent tuberculosis infection (LTBI).
REVIEW METHODS
Studies were selected and evaluated that (1) tested for LTBI, (2) compared tuberculin skin test (TST) and interferon-gamma assays based on ESAT-6 and CFP-10 antigens and (3) provided information on TB exposure or bacille Calmette-Guerin (BCG) vaccination or HIV status. For each test comparison, the sensitivity, specificity and 95% confidence intervals (CIs) were calculated. Sources of heterogeneity were investigated by adding covariates to the standard regression model. The authors examined whether interferon-gamma assays were more strongly associated with high versus low TB exposure than TST. Odds ratios (ORs) were calculated for the association between test results and exposures from each study along with their 95% CIs. Within each study, the OR value for one test was divided by that for another to produce a ratio of OR (ROR).
RESULTS
A total of 212 studies were included, providing 368 data sets. A further 19 studies assessing fully automated liquid culture were included. Overall, nucleic acid amplification test (NAAT) accuracy was far superior when applied to respiratory samples as opposed to other body fluids. The better quality in-house studies, were, for pulmonary TB, much better at ruling out TB than the commercial tests (higher sensitivity), but were less good at ruling it in (lower specificity), but it is not possible to recommend any one over another owing to a lack of direct test comparisons. The specificity of NAAT tests was high when applied to body fluids, for example for TB meningitis and pleural TB, but sensitivity was poor, indicating that these tests cannot be used reliably to rule out TB. High specificity estimates suggest that NAAT tests should be the first-line test for ruling in TB meningitis, but that they need to be combined with the result of other tests in order to rule out disease. Evidence for NAAT tests in other forms of TB and for phage-based tests is significantly less prolific than for those above and further research is needed to establish accuracy. There is no evidence to support the use of adenosine deaminase (ADA) tests for diagnosis of pulmonary TB; however, there is considerable evidence to support their use for diagnosis of pleural TB and to a slightly lesser extent for TB meningitis. Anti-TB antibody test performance was universally poor, regardless of type of TB. Fully automated liquid culture methods were superior to culture on solid media, in terms of their speed and their precision. In total, 13 studies were included. Assays based on RD1 specific antigens, ESAT-6 or CFP-10, correlate better with intensity of exposure, and therefore are more likely than TST/purified protein derivative (PPD)-based assays to detect LTBI accurately. An additional advantage is that they are more likely to be independent of BCG vaccination status and HIV status.
CONCLUSIONS
The NAAT tests provide a reliable way of increasing the specificity of diagnosis (ruling in disease) but sensitivity is too poor to rule out disease, especially in smear-negative (paucibacillary) disease where clinical diagnosis is equivocal and where the clinical need is greatest. For extra-pulmonary TB, clinical judgement has both poor sensitivity and specificity. For pleural TB and TB meningitis, adenosine deaminase tests have high sensitivity but limited specificity. NAATs have high specificity and could be used alongside ADA (or interferon-gamma) to increase sensitivity for ruling out disease and NAAT for high specificity to rule it in. All studies from low-prevalence countries strongly suggest that the RD1 antigen-based assays are more accurate than TST- and PPD-based assays for diagnosis of LTBI. If their superior diagnostic capability is found to hold up in routine clinical practice, they could confer several advantages on TB control programmes. Further research for active TB needs to establish diagnostic accuracy in a wide spectrum of patients, against an appropriate reference test, and avoiding the major sources of bias. For LTBI, research needs to address different epidemiological and clinical settings, to evaluate the performance of the main existing commercial assays in head-to-head comparison in both developed and developing countries, and to assess the role of adding more TB-specific antigens to try to improve diagnostic sensitivity.
Topics: Humans; Mycobacterium; Mycobacterium Infections, Nontuberculous; Tuberculin Test; Tuberculosis, Pulmonary; United Kingdom
PubMed: 17266837
DOI: 10.3310/hta11030