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1.  Effects of Gender and Age on Development of Concurrent Extrapulmonary Tuberculosis in Patients with Pulmonary Tuberculosis: A Population Based Study 
PLoS ONE  2013;8(5):e63936.
Most cases of adult-onset tuberculosis (TB) result from reactivation of a pre-existing Mycobacterium tuberculosis infection. Mycobacterium tuberculosis usually invades the respiratory tract and most patients develop intrapulmonary TB; however, some patients develop concurrent pulmonary and extra-pulmonary TB. The purpose of the present study was to identify the demographic and clinical factors associated with an increased risk of concurrent extra-pulmonary diseases in patients with pulmonary TB. We compared patients who had isolated pulmonary TB with patients who had concurrent pulmonary and extra-pulmonary TB. We initially analyzed one-million randomly selected subjects from the population-based Taiwan National Health Insurance database. Based on analysis of 5414 pulmonary TB patients in this database, women were more likely than men to have concurrent extra-pulmonary TB (OR: 1.30, p = 0.013). A separate analysis of the Kaohsiung Medical University Hospital database, which relied on sputum culture-proven pulmonary TB, indicated that women were more likely than men to have concurrent extra-pulmonary TB (OR: 1.62, p = 0.039). There was no significant gender difference in extra-pulmonary TB for patients younger than 45 years in either database. However, for patients 45 years and older, women were more likely than men to have concurrent extra-pulmonary TB (insurance database: 9.0% vs. 6.8%, p = 0.016, OR: 1.36; hospital database: 27.3% vs. 16.0%, p = 0.008, OR = 1.98). Our results indicate that among patients who have pulmonary TB, older females have an increased risk for concurrent extra-pulmonary TB.
doi:10.1371/journal.pone.0063936
PMCID: PMC3661599  PMID: 23717513
2.  Comparative Evaluation of the New Gen-Probe Mycobacterium tuberculosis Amplified Direct Test and the Semiautomated Abbott LCx Mycobacterium tuberculosis Assay for Direct Detection of Mycobacterium tuberculosis Complex in Respiratory and Extrapulmonary Specimens 
Journal of Clinical Microbiology  1998;36(12):3601-3604.
Two commercial assays that detect Mycobacterium tuberculosis complex (MTB) in clinical specimens by rRNA target amplification (AMTDII) and ligase chain reaction (LCx) were evaluated. The tests were applied to 457 respiratory (n = 273) and extrapulmonary (n = 184) specimens collected from 357 patients. The results were compared with those of acid-fast staining and culture. The combination of culture and clinical diagnosis was considered to be the “gold standard.” Seventy specimens were from patients with pulmonary tuberculosis and 28 specimens were from patients with extrapulmonary tuberculosis. After resolution of discrepant results, the overall sensitivities, specificities, and positive and negative predictive values for respiratory specimens were 92.8, 99.4, 98.5, and 97%, respectively, for AMTDII and 75.7, 98.8, 96.4, and 90.5%, respectively, for LCx. With extrapulmonary specimens, the overall sensitivities, specificities, and positive and negative predictive values were 78.6, 99.3, 95.6, and 96.2%, respectively, for AMTDII and 53.6, 99.3, 93.7, and 92.1%, respectively, for LCx. The level of agreement between AMTDII and LCx assay results was 78.2%. We conclude that although both nucleic acid amplification methods are rapid and specific for the detection of MTB in clinical specimens, AMTDII is significantly more sensitive than LCx with both respiratory (P = 0.005) and extrapulmonary (P = 0.048) specimens.
PMCID: PMC105247  PMID: 9817880
3.  Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study [Supplementary Cholecalciferol in recovery from tuberculosis]. A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis’ 
Background
Vitamin D enhances host protective immune responses to Mycobacterium tuberculosis by suppressing Interferon-gamma (IFN-g) and reducing disease associated inflammation in the host. The objectives of this study were to determine whether vitamin D supplementation to patients with tuberculosis (TB) could influence recovery.
Methods
Two hundred and fifty nine patients with pulmonary TB were randomized to receive either 600,000 IU of Intramuscular vitamin D3 or placebo for 2 doses. Assessments were performed at 4, 8 and 12 weeks. Early secreted and T cell activated 6 kDa (ESAT6) and Mycobacterium tuberculosis sonicate (MTBs) antigen induced whole blood stimulated IFN-g responses were measured at 0 and 12 weeks. Statistical comparisons between outcome variables at 0 and 12 weeks were performed using Student’s t-test and Chi2 tests.
Results
After 12 weeks, the vitamin D supplemented arm demonstrated significantly greater mean weight gain (kg) + 3.75, (3.16 – 4.34) versus + 2.61 (95% CI 1.99 – 3.23) p 0.009 and lesser residual disease by chest radiograph; number of zones involved 1.35 v/s 1.82 p 0.004 (95% CI 0.15, 0.79) and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035. Vitamin D supplementation led to significant increase in MTBs-induced IFN-g secretion in patients with baseline ‘Deficient’ 25-hydroxyvitamin D serum levels (p 0.021).
Conclusions
Supplementation with high doses of vitamin D accelerated clinical, radiographic improvement in all TB patients and increased host immune activation in patients with baseline ‘Deficient’ serum vitamin D levels. These results suggest a therapeutic role for vitamin D in the treatment of TB.
Trial registration
ClinicalTrials.gov; No. NCT01130311; URL: clinicaltrials.gov
doi:10.1186/1471-2334-13-22
PMCID: PMC3556334  PMID: 23331510
4.  Tuberculosis Screening by Tuberculosis Skin Test or QuantiFERON®-TB Gold In-Tube Assay among an Immigrant Population with a High Prevalence of Tuberculosis and BCG Vaccination 
PLoS ONE  2013;8(12):e82727.
Rationale
Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross reaction with bacillus Calmette-Guérin (BCG), TST may yield false positive results in BCG-vaccinated persons. Interferon gamma release assays exclude antigens found in BCG. In Vietnam, like most high TB-prevalence countries, there is universal BCG vaccination at birth.
Objectives
1. Compare the sensitivity of QuantiFERON ®-TB Gold In-Tube Assay (QFT) and TST for culture-positive pulmonary TB. 2. Compare the age-specific and overall prevalence of positive TST and QFT among applicants with normal and abnormal CXR.
Methods
We obtained TST and QFT results on 996 applicants with abnormal CXR, of whom 132 had TB, and 479 with normal CXR.
Results
The sensitivity for tuberculosis was 86.4% for QFT; 89.4%, 81.1%, and 52.3% for TST at 5, 10, and 15 mm. The estimated prevalence of positive results at age 15–19 years was 22% and 42% for QFT and TST at 10 mm, respectively. The prevalence increased thereafter by 0.7% year of age for TST and 2.1% for QFT, the latter being more consistent with the increase in TB among applicants.
Conclusions
During 2-stage screening, QFT is as sensitive as TST in detecting TB with fewer requiring CXR and being diagnosed with LTBI. These data support the use of QFT over TST in this population. 
doi:10.1371/journal.pone.0082727
PMCID: PMC3868593  PMID: 24367546
5.  Genetic heterogeneity revealed by sequence analysis of Mycobacterium tuberculosis isolates from extra-pulmonary tuberculosis patients 
BMC Genomics  2013;14:404.
Background
Tuberculosis remains a major public health problem. Clinical tuberculosis manifests often as pulmonary and occasionally as extra-pulmonary tuberculosis. The emergence of drug resistant tubercle bacilli and its association with HIV is a formidable challenge to curb the spread of tuberculosis. There have been concerted efforts by whole genome sequencing and bioinformatics analysis to identify genomic patterns and to establish a relationship between the genotype of the organism and clinical manifestation of tuberculosis. Extra-pulmonary TB constitutes 15–20 percent of the total clinical cases of tuberculosis reported among immunocompetent patients, whereas among HIV patients the incidence is more than 50 percent. Genomic analysis of M. tuberculosis isolates from extra pulmonary patients has not been explored.
Results
The genomic DNA of 5 extra-pulmonary clinical isolates of M. tuberculosis derived from cerebrospinal fluid, lymph node fine needle aspirates (FNAC) / biopsies, were sequenced. Next generation sequencing approach (NGS) was employed to identify Single Nucleotide Variations (SNVs) and computational methods used to predict their consequence on functional genes. Analysis of distribution of SNVs led to the finding that there are mixed genotypes in patient isolates and that many SNVs are likely to influence either gene function or their expression. Phylogenetic relationship between the isolates correlated with the origin of the isolates. In addition, insertion sites of IS elements were identified and their distribution revealed a variation in number and position of the element in the 5 extra-pulmonary isolates compared to the reference M. tuberculosis H37Rv strain.
Conclusions
The results suggest that NGS sequencing is able to identify small variations in genomes of M. tuberculosis isolates including changes in IS element insertion sites. Moreover, variations in isolates of M. tuberculosis from non-pulmonary sites were documented. The analysis of our results indicates genomic heterogeneity in the clinical isolates.
doi:10.1186/1471-2164-14-404
PMCID: PMC3699378  PMID: 23773324
Extra-pulmonary Tuberculosis; Next-generation Sequencing; Genetic Heterogeneity; Single Nucleotide Variations; Insertion Elements; Phylogeny; Spoligotyping
6.  The Value of Routinely Culturing for Tuberculosis During Bronchoscopies in an Intermediate Tuberculosis-Burden Country 
Yonsei Medical Journal  2007;48(6):969-972.
Purpose
Many medical centers routinely culture bronchoscopy samples for Mycobacterium tuberculosis, even when tuberculosis is not strongly suspected. The value of this practice, however, is controversial. We evaluated the role of that procedure in the diagnosis of pulmonary tuberculosis in an intermediate tuberculosis-burden country.
Patients and Methods
A prospective, observational study was conducted in a tertiary referral center and included 733 consecutive patients who underwent bronchoscopy examination.
Results
M. tuberculosis was isolated in 47 patients (6.4%). According to radiographic features, the rate of positive culture for M. tuberculosis was relatively high in patients with atelectasis (5/33, 15.2%) and those with pulmonary infiltrations of suspicious infections (26/183, 14.2%). M. tuberculosis was isolated even in patients with pulmonary masses (9/266, 3.4%) and those with pulmonary nodules (5/175, 2.9%). In 16/47 (34.0%) patients with positive cultures for M. tuberculosis, active pulmonary tuberculosis was not suspected at the time of bronchoscopy.
Conclusion
These results suggest that routinely culturing for M. tuberculosis during bronchoscopy is still useful in the diagnosis of pulmonary tuberculosis in an intermediate tuberculosis-burden country.
doi:10.3349/ymj.2007.48.6.969
PMCID: PMC2628186  PMID: 18159588
Bronchoscopy; diagnosis; pulmonary tuberculosis
7.  Tuberculosis burden in China: a high prevalence of pulmonary tuberculosis in household contacts with and without symptoms 
Background
In the context of decreasing tuberculosis prevalence in China, we examined the effectiveness of screening household contacts of tuberculosis patients.
Methods
A tuberculosis survey was conducted in 2008. All 3,355 household contacts of notified tuberculosis cases were examined with a questionnaire interview, chest X-ray and three sputum smear tests. The effectiveness was examined by comparing the prevalence of pulmonary tuberculosis in household contacts with or without presenting clinical symptoms against the respective notification rates. Regression models were used to evaluate the factors associated with pulmonary tuberculosis.
Results
Of the 3,355 household contacts, 92 members (2.7%) had pulmonary tuberculosis, among which 46 cases were asymptomatic. The prevalence of pulmonary tuberculosis and smear positive cases in household contacts without symptoms were 20 and 7 times higher than the notification rates in 2008, while those in household contacts with symptoms were 247 and 108 times higher than notification rates, respectively. The patients detected were mainly Index Cases’ spouses, sisters/brothers and those who were in contact with female Index Cases.
Conclusions
The present study provides convincing evidence that household contacts of notified tuberculosis cases are at higher risk of developing tuberculosis. Routine screening for household contacts without any symptoms is recommended for sustained tuberculosis control in China as well as in the world.
doi:10.1186/1471-2334-14-64
PMCID: PMC3918223  PMID: 24502559
Tuberculosis; Household contact; Index cases
8.  Changes in Avidity and Level of Immunoglobulin G Antibodies to Mycobacterium tuberculosis in Sera of Patients Undergoing Treatment for Pulmonary Tuberculosis 
Much is known about specific antibodies and their titers in patients with tuberculosis. However, little is known about the avidity of these antibodies or whether changes in avidity occur during the progression of the disease or during treatment. The aims of this study were to determine the avidity of antibodies to Mycobacterium tuberculosis in patients with pulmonary tuberculosis, to explore the value of avidity determination for the diagnosis of tuberculosis, and to study changes in levels of antibodies and their avidity during treatment. Antibody avidity was measured by an enzyme-linked immunosorbent assay with thiocyanate elution. Avidity indices and serum levels of immunoglobulin G to M. tuberculosis were determined for 22 patients with pulmonary tuberculosis before and during treatment and for 24 patients with other pulmonary diseases. Antibody levels and avidity were both significantly higher in untreated tuberculosis patients than in the controls. Avidity determination had more diagnostic potential than determination of the antibody levels. Tuberculosis patients with a long duration of symptoms had higher antibody avidity than those with a recent onset of symptoms, indicating affinity maturation of specific antibodies during active disease. In the early phase of treatment, a decrease in antibody avidity was observed for 73% of all tuberculosis patients, accompanied by an initial increase in antibody levels in 36% of these patients. These phenomena could be explained by an intense stimulation of the humoral response by antigens released from killed bacteria, reflecting early bactericidal activity of antituberculous drugs leading to the production of low-affinity antibodies against these released antigens.
doi:10.1128/CDLI.10.4.702-709.2003
PMCID: PMC164257  PMID: 12853408
9.  Relationship between Mycobacterium tuberculosis Genotype and the Clinical Phenotype of Pulmonary and Meningeal Tuberculosis ▿  
Journal of Clinical Microbiology  2008;46(4):1363-1368.
We used large sequence polymorphisms to determine the genotypes of 397 isolates of Mycobacterium tuberculosis from human immunodeficiency virus-uninfected Vietnamese adults with pulmonary (n = 235) or meningeal (n = 162) tuberculosis. We compared the pretreatment radiographic appearances of pulmonary tuberculosis and the presentation, response to treatment, and outcome of tuberculous meningitis between the genotypes. Multivariate analysis identified variables independently associated with genotype and outcome. A higher proportion of adults with pulmonary tuberculosis caused by the Euro-American genotype had consolidation on chest X-ray than was the case with disease caused by other genotypes (P = 0.006). Multivariate analysis revealed that meningitis caused by the East Asian/Beijing genotype was independently associated with a shorter duration of illness before presentation and fewer cerebrospinal fluid (CSF) leukocytes. Older age, fewer CSF leukocytes, and the presence of hemiplegia (but not strain lineage) were independently associated with death or severe disability, although the East Asian/Beijing genotype was strongly associated with drug-resistant tuberculosis. The genotype of M. tuberculosis influenced the presenting features of pulmonary and meningeal tuberculosis. The association between the East Asian/Beijing lineage and disease progression and CSF leukocyte count suggests the lineage may alter the presentation of meningitis by influencing the intracerebral inflammatory response. In addition, increased drug resistance among bacteria of the East Asian/Beijing lineage might influence the response to treatment. This study suggests the genetic diversity of M. tuberculosis has important clinical consequences.
doi:10.1128/JCM.02180-07
PMCID: PMC2292951  PMID: 18287322
10.  Tuberculosis and patient gender: An analysis and its implications in tuberculosis control 
Objective:
To analyze the profile of pulmonary tuberculosis patients with respect to gender and its implications in tuberculosis control. Setting: DOTS center at a tertiary, teaching hospital in South India.
Materials and Methods:
A retrospective study was undertaken by screening medical records of 446 patients with pulmonary tuberculosis. Data studied included age, gender, and sputum smear status. Patients with comorbid conditions were excluded. No other data were considered.
Results:
The male to female ratio in patients of pulmonary tuberculosis was 2:1, which was also maintained when smear positive and smear negative were studied separately. The ratio of smear positive to smear negative patients was statistically significant at 4.4:1. A large proportion of patients (65–68%) were in the young and reproductive age group. Approximately, one-fifth patients were in the geriatric age group.
Conclusion:
The observation that two-thirds of all female smear-positive patients were found in the young and reproductive age group has strong implications in tuberculosis control strategies because of higher chances of mother to child transmission and higher probability of complications because of attendant antenatal and postnatal morbidity. Geriatric patients comprise another significant group because of higher chances of default, complications, inconvenience, and existence of other comorbid conditions.
doi:10.4103/0970-2113.48897
PMCID: PMC2860414  PMID: 20440394
Tuberculosis; gender; control; reproductive health
11.  Prevalence of multidrug-resistant tuberculosis among Category II pulmonary tuberculosis patients 
Background & objectives:
Multidrug-resistant tuberculosis (MDR-TB) has emerged as a significant global health concern. The most important risk factor for the development of MDR-TB is previous anti-tuberculosis therapy. Category II pulmonary TB includes those patients who had failed previous TB treatment, relapsed after treatment, or defaulted during previous treatment. We carried out this study to ascertain the prevalence of MDR-TB among category II pulmonary TB patients.
Methods:
This was a cross-sectional, descriptive study involving category II pulmonary TB patients diagnosed between 2005 and 2008. All sputum-positive category II TB cases were subjected to mycobacterial culture and drug-susceptibility testing (DST). MDR-TB was defined as TB caused by bacilli showing resistance to at least isoniazid and rifampicin.
Results:
A total of 196 cases of sputum-positive category II pulmonary tuberculosis patients were included. Of these, 40 patients (20.4%) had MDR-TB. The mean age of MDR-TB patients was 33.25 ± 12.04 yr; 9 patients (22.5%) were female. Thirty six patients showed resistance to rifampicin and isoniazid; while 4 patients showed resistance to rifampicin, isoniazid and streptomycin. The prevalence of MDR-TB among category-II pulmonary tuberculosis patients was 20.4 per cent.
Interpretation & conclusions :
The prevalence of MDR-TB in category II TB patients was significant. However, nation-wide and State-wide representative data on prevalence of MDR-TB are lacking. We stress the importance of continuous monitoring of drug resistance trends, in order to assess the efficacy of current interventions and their impact on the TB epidemic.
PMCID: PMC3103157  PMID: 21441686
Category II patients; India; multidrug-resistant tuberculosis; previously treated TB patients; pulmonary tuberculosis
12.  Prevalence of presumed ocular tuberculosis among pulmonary tuberculosis patients in a tertiary hospital in the Philippines 
Background
The objective of this study was to determine the prevalence of presumed ocular tuberculosis among diagnosed pulmonary tuberculosis patients in a tertiary government hospital in the Philippines and determine its common presentation in the population. This was a cross-sectional study in which 103 patients who were labeled to have active pulmonary tuberculosis underwent history and ocular examination prior to anti-tubercular therapy. The diagnosis of presumed ocular tuberculosis was made when clinical signs of tuberculosis (TB) uveitis were found in the participants. Lesions were documented and tallied, after which statistical analysis was performed.
Results
Seven out of the 103 pulmonary TB patients (6.8% prevalence: 95% CI 2.78% to 13.5%) included in the study showed signs of ocular inflammation. There was no sex and age predilection between those with presumed ocular TB and those without. Posterior uveitis alone was observed in three of the patients (two cases of retinal vasculitis and one case of choroidal tubercle). Non-granulomatous anterior uveitis with posterior synechiae alone was observed in two patients. One patient had combined non-granulomatous anterior uveitis with posterior synechiae and choroidal tubercle. One had combined granulomatous anterior uveitis with posterior synechiae and choroidal tubercle. Intermediate uveitis was not noted among the patients.
Conclusions
Presumed ocular tuberculosis should be considered among patients with diagnosed pulmonary tuberculosis. Common ocular lesions found in the study include choroidal tubercle and non-granulomatous anterior uveitis with posterior synechiae.
doi:10.1186/1869-5760-3-1
PMCID: PMC3589205  PMID: 23514121
Presumed ocular tuberculosis; Prevalence; Anti-tubercular therapy; Extra-pulmonary TB; Anterior uveitis; Posterior uveitis
13.  Tuberculosis associated with Mycobacterium tuberculosis Beijing and non-Beijing genotypes: a clinical and immunological comparison 
Background
The Mycobacterium tuberculosis Beijing genotype is biologically different from other genotypes. We aimed to clinically and immunologically compare human tuberculosis caused by Beijing and non-Beijing strains.
Methods
Pulmonary tuberculosis patients were prospectively enrolled and grouped by their M. tuberculosis genotypes. The clinical features, plasma cytokine levels, and cytokine gene expression levels in peripheral blood mononuclear cells (PBMC) were compared between the patients in Beijing and non-Beijing groups.
Results
Patients in the Beijing group were characterized by significantly lower frequency of fever (odds ratio, 0.12, p = 0.008) and pulmonary cavitation (odds ratio, 0.2, p = 0.049). Night sweats were also significantly less frequent by univariate analysis, and the duration of cough prior to diagnosis was longer in Beijing compared to non-Beijing groups (medians, 60 versus 30 days, p = 0.048). The plasma and gene expression levels of interferon (IFN) γ and interleukin (IL)-18 were similar in the two groups. However, patients in the non-Beijing group had significantly increased IL-4 gene expression (p = 0.018) and lower IFN-γ : IL-4 cDNA copy number ratios (p = 0.01).
Conclusion
Patients with tuberculosis caused by Beijing strains appear to be less symptomatic than those who have disease caused by other strains. Th1 immune responses are similar in patients infected with Beijing and non-Beijing strains, but non-Beijing strains activate more Th2 immune responses compared with Beijing strains, as evidenced by increased IL-4 expression.
doi:10.1186/1471-2334-6-105
PMCID: PMC1552074  PMID: 16820066
14.  Diabetes and tuberculosis: the impact of the diabetes epidemic on tuberculosis incidence 
BMC Public Health  2007;7:234.
Background
Tuberculosis (TB) remains a major cause of mortality in developing countries, and in these countries diabetes prevalence is increasing rapidly. Diabetes increases the risk of TB. Our aim was to assess the potential impact of diabetes as a risk factor for incident pulmonary tuberculosis, using India as an example.
Methods
We constructed an epidemiological model using data on tuberculosis incidence, diabetes prevalence, population structure, and relative risk of tuberculosis associated with diabetes. We evaluated the contribution made by diabetes to both tuberculosis incidence, and to the difference between tuberculosis incidence in urban and rural areas.
Results
In India in 2000 there were an estimated 20.7 million adults with diabetes, and 900,000 incident adult cases of pulmonary tuberculosis. Our calculations suggest that diabetes accounts for 14.8% (uncertainty range 7.1% to 23.8%) of pulmonary tuberculosis and 20.2% (8.3% to 41.9%) of smear-positive (i.e. infectious) tuberculosis.
We estimate that the increased diabetes prevalence in urban areas is associated with a 15.2% greater smear-positive tuberculosis incidence in urban than rural areas – over a fifth of the estimated total difference.
Conclusion
Diabetes makes a substantial contribution to the burden of incident tuberculosis in India, and the association is particularly strong for the infectious form of tuberculosis. The current diabetes epidemic may lead to a resurgence of tuberculosis in endemic regions, especially in urban areas. This potentially carries a risk of global spread with serious implications for tuberculosis control and the achievement of the United Nations Millennium Development Goals.
doi:10.1186/1471-2458-7-234
PMCID: PMC2001194  PMID: 17822539
15.  T-Cell Responses to the Mycobacterium tuberculosis-Specific Antigen ESAT-6 in Brazilian Tuberculosis Patients  
Infection and Immunity  2002;70(12):6707-6714.
The Mycobacterium tuberculosis-specific ESAT-6 antigen induces highly potent T-cell responses and production of gamma interferon (IFN-γ), which play a critical role in protective cell-mediated immunity against tuberculosis (TB). In the present study, IFN-γ secretion by peripheral blood mononuclear cells (PBMCs) in response to M. tuberculosis ESAT-6 in Brazilian TB patients was investigated in relation to clinical disease types, such as pleurisy and cavitary pulmonary TB. Leprosy patients, patients with pulmonary diseases other than TB, and healthy donors were assayed as control groups. Sixty percent of the TB patients indeed recognized M. tuberculosis ESAT-6, as did 50% of the leprosy patients and 60% of the non-TB controls. Nevertheless, the levels of IFN-γ in response to the antigen ESAT, but not to antigen 85B (Ag85B) and purified protein derivative (PPD), were significantly lower in controls than in patients with treated TB or pleural or cavitary TB. Moreover, according to Mycobacterium bovis BCG vaccination status, only 59% of the vaccinated TB patients responded to ESAT in vitro, whereas 100% of them responded to PPD. Both CD4 and CD8 T cells were able to release IFN-γ in response to ESAT. The present data demonstrate the specificity of ESAT-6 of M. tuberculosis and its ability to discriminate TB patients from controls, including leprosy patients. However, to obtain specificity, it is necessary to include quantitative IFN-γ production in response to the antigen as well, and this might limit the use of ESAT-6-based immunodiagnosis of M. tuberculosis infection in an area of TB endemicity.
doi:10.1128/IAI.70.12.6707-6714.2002
PMCID: PMC132944  PMID: 12438345
16.  Immunoblot analysis for serodiagnosis of tuberculosis using a 45/47-kilodalton antigen complex of Mycobacterium tuberculosis. 
We evaluated the immunoglobulin G (IgG) antibody response to the 45/47-kDa secreted protein of Mycobacterium tuberculosis by immunoblot assay, to assess its potential value for serological diagnosis. Control subjects consisted of healthy volunteers with negative or positive tuberculin skin tests. Most (>98%) scored negative in an immunoblot test when the sera were analyzed at a 1:400 dilution. Approximately 40% of sera (diluted 1 in 400) from tuberculous patients (positive smears) recognized the antigen complex. The sensitivity of the test for patients suffering from extrapulmonary tuberculosis was similar to that for patients suffering from pulmonary tuberculosis but who had negative smears. The frequency of positive reactions among the patients suffering from other pulmonary diseases was similar to that among the control subjects. In tuberculous patients infected with human immunodeficiency virus, the sensitivity of the immunoblot test was significantly lower. Thus, this test based on an antigen complex used in an immunoblot assay to detect the presence of IgG antibody has a specificity of 98% and a sensitivity of 40%. The simultaneous use of different purified antigens, selected at the same high specificity level, may improve the sensitivity of such an assay.
PMCID: PMC170528  PMID: 9144373
17.  Detection of pulmonary and extrapulmonary tuberculosis patients with the 38-kilodalton antigen from Mycobacterium tuberculosis in a rapid membrane-based assay. 
A rapid membrane-based serologic assay using the 38-kDa antigen from Mycobacterium tuberculosis for the diagnosis of tuberculosis (TB) was evaluated with 201 patients with pulmonary TB, 67 patients with extrapulmonary TB, 79 Mycobacterium bovis BCG-vaccinated healthy controls, and 77 non-TB respiratory patients. The overall sensitivities, specificities, and positive and negative predictive values were, respectively, 92, 92, 84, and 96% for sputum-positive TB patients; 70, 92, 87, and 79% for sputum-negative TB patients; and 76, 92, 80, and 90% for extrapulmonary-TB patients. Only 2% (1 of 44) of the healthy control BCG-vaccinated subjects gave weak positive signals in the assay, indicating that this rapid serological assay is a valuable aid in clinical diagnosis for both pulmonary and extrapulmonary TB.
PMCID: PMC170343  PMID: 8705680
18.  Evaluation of the semiautomated Abbott LCx Mycobacterium tuberculosis assay for direct detection of Mycobacterium tuberculosis in respiratory specimens. 
Journal of Clinical Microbiology  1997;35(8):1996-2002.
Five hundred twenty processed respiratory specimens from 326 patients received for the diagnosis of tuberculosis or other mycobacterial infections were tested by means of the LCx Mycobacterium tuberculosis Assay from Abbott Laboratories, which uses ligase chain reaction technology for the direct detection of M. tuberculosis complex in respiratory specimens. The results of the LCx M. tuberculosis Assay were compared with the results of culture and staining techniques. After a combination of culture results and the patient's clinical data, a total of 195 specimens were collected from 110 patients who were positively diagnosed as having pulmonary tuberculosis. Twenty-three of these 195 specimens which corresponded to 10 patients with a history of pulmonary tuberculosis (TB) and anti-TB treatment ranging from 1 to 6 months were culture negative. The other 172 specimens were culture positive for M. tuberculosis. With an overall positivity rate of 37.5% (195 of 520 specimens), the sensitivity, specificity, and positive and negative predictive values were 90.8, 100, 100, and 94.7%, respectively, for the LCx M. tuberculosis Assay; 88.2, 100, 100, and 93.4%, respectively, for culture; and 82.6, 92, 72.9, and 97.6%, respectively, for acid-fast staining. For 161 specimens (82.6%) from patients smear positive for the disease and 34 specimens (17.4%) from patients smear negative for the disease, the sensitivity values for the LCx M. tuberculosis Assay were 98.8 and 53%, respectively. There were no statistically significant differences in the sensitivities and specificities between the LCx M. tuberculosis Assay and culture (P > 0.05). Conclusively, the LCx M. tuberculosis Assay has proved to have an acceptable sensitivity and a high specificity in detecting M. tuberculosis and has the potential of reducing the diagnosis time to an 8-h working day.
PMCID: PMC229890  PMID: 9230369
19.  Clinical value of the measurement of Mycobacterium tuberculosis specific antibody in pulmonary tuberculosis. 
Thorax  1992;47(4):270-275.
BACKGROUND: A serological test that could help to diagnose tuberculosis, especially smear negative disease, would contribute to patient management. METHODS: Levels of antibody to distinct antigens of Mycobacterium tuberculosis were assessed for their value in the diagnosis and management of pulmonary tuberculosis. Serum was taken from 52 patients who were smear positive, from 27 patients who were smear negative but with evidence of active tuberculosis (sputum culture positive in 16, response to antituberculosis chemotherapy in 11), from 11 patients with old healed tuberculosis (pre-antibiotic era), and from 39 healthy subjects vaccinated with BCG. RESULTS: In smear positive tuberculosis an enzyme linked immunosorbent assay using a single 38 kDa antigen gave a diagnostic sensitivity of 80% with a 100% specificity. In smear negative pulmonary tuberculosis, however, combination of the 19 kDa antigen, lipoarabinomannan (ML 34 epitope), and hsp 65 (TB 78 epitope) was needed to achieve a sensitivity of 64% with a specificity of 95%. Recurrent and extensive radiographic disease with a poor prognosis was associated with high anti-38 kDa and low anti-14 kDa antibody levels in patients with active disease. Patients with less pulmonary cavitation had high anti-19 kDa titres. Bacteriological relapse during treatment was indicated by a rise in anti-14 kDa (TB68 epitope) antibodies. Four patients with non-tuberculous mycobacterial infection showed no anti-38 kDa antibody. CONCLUSION: Antigen or epitope specific serology may help in the diagnosis, assessment of prognosis, and monitoring of chemotherapy in patients with pulmonary tuberculosis.
PMCID: PMC463688  PMID: 1585290
20.  Tuberculosis and renal transplantation--observations from an endemic area of tuberculosis. 
Postgraduate Medical Journal  1986;62(727):359-362.
Ninety-five renal transplant recipients from an endemic area of tuberculosis were investigated to find out the prevalence and course of tuberculosis in pre- and post-transplant periods. Eleven patients had tuberculosis in the pre-transplant period - pulmonary (2), pleural (2), miliary (1), abdominal (2), lymph node (5) and pericardial (1). They were transplanted after antituberculous therapy of 3 to 6 months with satisfactory results. The anti-tuberculous treatment was usually continued for 2 years. Only one of the above 11 patients had evidence of tuberculosis in the post-transplant period. Nine patients developed tuberculosis for the first time in the post-transplant period - pulmonary (4), pleural (1), miliary (1), lymph node (4) and pericardial (1). There was no mortality due to tuberculosis. Thorough search for tuberculosis is mandatory both during pre-transplant assessment and post-transplant follow-up in areas of endemic tuberculosis.
PMCID: PMC2418707  PMID: 3532083
21.  Unique Transcriptome Signature of Mycobacterium tuberculosis in Pulmonary Tuberculosis†  
Infection and Immunity  2006;74(2):1233-1242.
Although tuberculosis remains a substantial global threat, the mechanisms that enable mycobacterial persistence and replication within the human host are ill defined. This study represents the first genome-wide expression analysis of Mycobacterium tuberculosis from clinical lung samples, which has enabled the identification of M. tuberculosis genes actively expressed during pulmonary tuberculosis. To obtain optimal information from our DNA array analyses, we analyzed the differentially expressed genes within the context of computationally inferred protein networks. Protein networks were constructed using functional linkages established by the Rosetta stone, phylogenetic profile, conserved gene neighbor, and operon computational methods. This combined approach revealed that during pulmonary tuberculosis, M. tuberculosis actively transcribes a number of genes involved in active fortification and evasion from host defense systems. These genes may provide targets for novel intervention strategies.
doi:10.1128/IAI.74.2.1233-1242.2006
PMCID: PMC1360294  PMID: 16428773
22.  Tuberculosis burden in an urban population: a cross sectional tuberculosis survey from Guinea Bissau 
Background
Little is known about the prevalence of pulmonary tuberculosis (TB) in low income countries. We conducted a cross sectional survey for pulmonary TB and TB symptoms in Bissau, Guinea-Bissau, in an urban cohort with known HIV prevalence. TB surveillance in the area is routinely based on passive case finding.
Methods
Two cohorts were selected based on a previous HIV survey, but only 52.5% of those enrolled in the adult cohort had participated in the HIV survey. One cohort included all adults living in 384 randomly selected houses; in this cohort 8% (135/1687) were HIV infected. The other included individuals 50 years or older from all other houses in the study area; of these 11% (62/571) were HIV infected. Symptom screening was done through household visits using a standardised questionnaire. TB suspects were investigated with sputum smear microscopy and X-ray.
Results
In the adult cohort, we found 4 cases among 2989 individuals screened, giving a total TB prevalence of 134/100,000 (95% CI 36-342/100,000). In the >50 years cohort, we found 4 cases among 571 individuals screened, giving a total prevalence of 701/100,000 (191-1784/100.000). Two of the eight detected TB cases were unknown by the TB program. Of the total TB cases five were HIV uninfected while three had unknown HIV status. The prevalence of TB symptoms was 2.1% (63/2989) and 10.3% (59/571) in the two cohorts respectively.
Conclusions
In conclusion we found a moderately high prevalence of pulmonary TB and TB symptoms in the general population, higher among elderly individuals. By active case finding unknown cases were detected. Better awareness of TB and its symptoms needs to be promoted in low income settings.
doi:10.1186/1471-2334-10-96
PMCID: PMC2860354  PMID: 20398388
23.  Evaluation of Molecular Tools for Detection and Drug Susceptibility Testing of Mycobacterium tuberculosis in Stool Specimens from Patients with Pulmonary Tuberculosis ▿  
Journal of Clinical Microbiology  2010;48(5):1820-1826.
Pulmonary tuberculosis diagnosis is difficult when patients cannot produce sputum. Most sputum is swallowed, and tuberculosis DNA can survive intestinal transit. We therefore evaluated molecular testing of stool specimens for detecting tuberculosis originating from the lungs. Paired stool and sputum samples (n = 159) were collected from 89 patients with pulmonary tuberculosis. Control stool samples (n = 47) were collected from patients without tuberculosis symptoms. Two techniques for DNA extraction from stool samples were compared, and the diagnostic accuracy of the PCR in stool was compared with the accuracy of sputum testing by PCR, microscopy, and culture. A heminested IS6110-PCR was used for tuberculosis detection, and IS6110-PCR-positive stool samples then underwent rifampin sensitivity testing by universal heteroduplex generator PCR (heteroduplex-PCR) assay. For newly diagnosed pulmonary tuberculosis patients, stool IS6110-PCR had 86% sensitivity and 100% specificity compared with results obtained by sputum culture, and stool PCR had similar sensitivities for HIV-positive and HIV-negative patients (P = 0.3). DNA extraction with commercially available spin columns yielded greater stool PCR sensitivity than DNA extraction with the in-house Chelex technique (P = 0.007). Stool heteroduplex-PCR had 98% agreement with the sputum culture determinations of rifampin resistance and multidrug resistance. Tuberculosis detection and drug susceptibility testing by stool PCR took 1 to 2 days compared with an average of 9 weeks to obain those results by traditional culture-based testing. Stool PCR was more sensitive than sputum microscopy and remained positive for most patients for more than 1 week of treatment. In conclusion, stool PCR is a sensitive, specific, and rapid technique for the diagnosis and drug susceptibility testing of pulmonary tuberculosis and should be considered when sputum samples are unavailable.
doi:10.1128/JCM.01161-09
PMCID: PMC2863910  PMID: 20200293
24.  High Frequency of First-Line Anti-Tuberculosis Drug Resistance among Persons with Chronic Pulmonary Tuberculosis at a Teaching Hospital Chest Clinic 
Ghana Medical Journal  2010;44(2):42-46.
Summary
Introduction
The burden of MDR-TB is unknown in areas that do not have drug susceptibility testing (DST), but its frequency is expected to be higher in previously treated cases. Where DST is not available the WHO recommended standardized retreatment (Category II) regimen is given to previously treated TB patients
Objective
To evaluate the frequency and pattern of drug resistance of Mycobacterium tuberculosis isolated from patients with chronic smear positive pulmonary tuberculosis.
Method
We conducted a retrospective review of mycobacterial cultures and drug susceptibility testing (DST) performed on sputum samples collected, between January 2005 and September 2006, from 40 patients with pulmonary TB who had failed at least one standard retreatment regimen. Clinical data was extracted from patients' case notes.
Results
M. tuberculosis was recovered from 28 (70%) of the 40 patients. Of the 28 culture positive cases, 10 (36%) had resistance to at least rifampicin and isoniazid (multi-drug resistant TB), 22 (79%) isolates had resistance to streptomycin and 13 (46%) to ethambutol. Of the patients with a positive culture, only one (3.6%) had a fully susceptible organism. Of the 10 patients with MDR TB, 7 had received two or more retreatment courses.
Conclusion
The frequency of drug resistant TB was high among patients who failed at least one course of category II therapy. Effective combination regimens based on DST is necessary in patients who remain smear positive on the standardized retreatment regimen.
PMCID: PMC2994151  PMID: 21327002
drug-resistance; MDR; chronic TB; re-treatment regimen
25.  Cost implications of delays to tuberculosis diagnosis among pulmonary tuberculosis patients in Ethiopia 
BMC Public Health  2010;10:173.
Background
Delays seeking care worsen the burden of tuberculosis and cost of care for patients, families and the public health system. This study investigates costs of tuberculosis diagnosis incurred by patients, escorts and the public health system in 10 districts of Ethiopia.
Methods
New pulmonary tuberculosis patients ≥ 15 years old were interviewed regarding their health care seeking behaviour at the time of diagnosis. Using a structured questionnaire patients were interviewed about the duration of delay at alternative care providers and the public health system prior to diagnosis. Costs incurred by patients, escorts and the public health system were quantified through patient interview and review of medical records.
Results
Interviews were held with 537 (58%) smear positive patients and 387 (42%) smear negative pulmonary patients. Of these, 413 (45%) were female; 451 (49%) were rural residents; and the median age was 34 years. The mean (median) days elapsed for consultation at alternative care providers and public health facilities prior to tuberculosis diagnosis was 5 days (0 days) and 3 (3 days) respectively. The total median cost incurred from first consultation to diagnosis was $27 per patient (mean = $59). The median costs per patient incurred by patient, escort and the public health system were $16 (mean = $29), $3 (mean = $23) and $3 (mean = $7) respectively. The total cost per patient diagnosed was higher for women, rural residents; those who received government food for work support, patients with smear negative pulmonary tuberculosis and patients who were not screened for TB in at least one district diagnostic centers.
Conclusions
The costs of tuberculosis diagnosis incurred by patients and escorts represent a significant portion of their monthly income. The costs arising from time lost in seeking care comprised a major portion of the total cost of diagnosis, and may worsen the economic position of patients and their families. Getting treatment from alternative sources and low index of suspicion public health providers were key problems contributing to increased cost of tuberculosis diagnosis. Thus, the institution of effective systems of referral, ensuring screening of suspects across the district public health system and the involvement of alternative care providers in district tuberculosis control can reduce delays and the financial burden to patients and escorts.
doi:10.1186/1471-2458-10-173
PMCID: PMC3091545  PMID: 20353567

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