Magnitude of Mycobacterium tuberculosis transmission among household and non-household contacts of TB patients.

The household and non-household contacts of patients with tuberculosis (TB) face varying degrees of risk of infection by Mycobacterium tuberculosis. To quantify new infection and to determine the risk factors associated with new infection among named contacts in San Francisco, CA, USA. We performed a cohort study in patients with culture-positive pulmonary TB. We analyzed patient, contact, environmental and bacterial characteristics. Of the 2422 contacts named by 256 patients, 149 (6.2%) had new infection due to recent transmission from 79 (30.9%) patients. Of the 149 new infections, 87 (58.4%) occurred among household contacts and 62 (41.6%) among non-household contacts. Numerous acid-fast bacilli in sputum (odds ratio [OR] 2.64, 95%CI 1.32-5.25) and contacts being named by more than one patient (OR 2.90, 95%CI 1.23-6.85) were associated with new infection among household contacts. Being older than 50 years (OR 1.93, 95%CI 1.09-3.41) and an Asian/Pacific Islander (OR 3.09, 95%CI 1.50-6.37) were associated with new infection among non-household contacts. Fewer than one third of patients caused new infection to his/her contacts. A substantial proportion of transmission resulting in new infection occurred outside of the household. The risk factors for infection among household and non-household contacts are different and should be considered when prioritizing control interventions. .

Interplay of strain and race/ethnicity in the innate immune response to M. tuberculosis.

BACKGROUND: The roles of host and pathogen factors in determining innate immune responses to M. tuberculosis are not fully understood. In this study, we examined host macrophage immune responses of 3 race/ethnic groups to 3 genetically and geographically diverse M. tuberculosis lineages. METHODS: Monocyte-derived macrophages from healthy Filipinos, Chinese and non-Hispanic White study participants (approximately 45 individuals/group) were challenged with M. tuberculosis whole cell lysates of clinical strains Beijing HN878 (lineage 2), Manila T31 (lineage 1), CDC1551 (lineage 4), the reference strain H37Rv (lineage 4), as well as with Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA) and TLR4 agonist lipopolysaccharide (TLR4/LPS). Following overnight incubation, multiplex assays for nine cytokines: IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα, and GM-CSF, were batch applied to supernatants. RESULTS: Filipino macrophages produced less IL-1, IL-6, and more IL-8, compared to macrophages from Chinese and Whites. Race/ethnicity had only subtle effects or no impact on the levels of IL-10, IL-12p70, TNFα and GM-CSF. In response to the Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA), Filipino macrophages again had lower IL-1 and IL-6 responses and a higher IL-8 response, compared to Chinese and Whites. The TLR2/LTA-stimulated Filipino macrophages also produced lower amounts of IL-10, TNFα and GM-CSF. Race/ethnicity had no impact on IL-12p70 levels released in response to TLR2/LTA. The responses to TLR4 agonist lipopolysaccharide (TLR4/LPS) were similar to the TLR2/LTA responses, for IL-1, IL-6, IL-8, and IL-10. However, TLR4/LPS triggered the release of less IL-12p70 from Filipino macrophages, and less TNFα from White macrophages. CONCLUSIONS: Both host race/ethnicity and pathogen strain influence the innate immune response. Such variation may have implications for the development of new tools across TB therapeutics, immunodiagnostics and vaccines.

Clinical and bacteriological characteristics associated with clustering of multidrug-resistant tuberculosis.

SETTING: The impact of the genetic characteristics of Mycobacterium tuberculosis on the clustering of multidrug-resistant tuberculosis (MDR-TB) has not been analyzed together with clinical and demographic characteristics. OBJECTIVE: To determine factors associated with genotypic clustering of MDR-TB in a community-based study. DESIGN: We measured the proportion of clustered cases among MDR-TB patients and determined the impact of clinical and demographic characteristics and that of three M. tuberculosis genetic characteristics: lineage, drug resistance-associated mutations, and rpoA and rpoC compensatory mutations. RESULTS: Of 174 patients from California and Texas included in the study, the number infected by East-Asian, Euro-American, Indo-Oceanic and East-African-Indian M. tuberculosis lineages were respectively 70 (40.2%), 69 (39.7%), 33 (19.0%) and 2 (1.1%). The most common mutations associated with isoniazid and rifampin resistance were respectively katG S315T and rpoB S531L. Potential compensatory mutations in rpoA and rpoC were found in 35 isolates (20.1%). Hispanic ethnicity (OR 26.50, 95%CI 3.73-386.80), infection with an East-Asian M. tuberculosis lineage (OR 30.00, 95%CI 4.20-462.40) and rpoB mutation S531L (OR 4.03, 95%CI 1.05-23.10) were independent factors associated with genotypic clustering. CONCLUSION: Among the bacterial factors studied, East-Asian lineage and rpoB S531L mutation were independently associated with genotypic clustering, suggesting that bacterial factors have an impact on the ability of M. tuberculosis to cause secondary cases.

Impact of Euro-American sublineages of Mycobacterium tuberculosis on new infections among named contacts.

BACKGROUND: The impact of demographic, clinical, and bacterial factors on new infection by Euro-American lineage Mycobacterium tuberculosis among contacts of patients with tuberculosis (TB) has not been evaluated. OBJECTIVE: To describe the risk factors for new infection by Euro-American M. tuberculosis sublineages in San Francisco, California. DESIGN: We included contacts of patients with TB due to Euro-American M. tuberculosis. Sublineages were determined by large-sequence polymorphisms. We used tuberculin skin testing or QuantiFERON®-TB Gold In-Tube to identify contacts with new infection. Regression models with generalized estimating equations were used to determine the risk factors for new infection. RESULTS: We included 1488 contacts from 134 patients with TB. There were 79 (5.3%) contacts with new infection. In adjusted analyses, contacts of patients with TB due to region of difference 219 M. tuberculosis sublineage were less likely to have new infection (OR 0.23, 95%CI 0.06-0.84) than those with other sublineages. Other risk factors for new infection were contacts exposed to more than one patient with TB, contacts exposed for 30 days, or contacts with a history of smoking or excessive alcohol consumption. CONCLUSIONS: In addition to well-known exposure and clinical characteristics, bacterial characteristics independently contribute to the transmissibility of TB in San Francisco.

Treatment of non-cavitary pulmonary tuberculosis with shortened fluoroquinolone-based regimens: a meta-analysis.

SETTING: Several recent trials evaluating 4-month fluoroquinolone (FQ) containing regimens found that none of the experimental regimens were non-inferior to standard 6-month therapy in treating patients with drug-susceptible pulmonary tuberculosis (PTB). OBJECTIVE: To answer whether FQ-containing duration-shortened regimens are non-inferior to standard therapy in the treatment of patients with non-cavitary PTB. DESIGN: Systematic review of all randomized and quasi-randomized trials that substituted an FQ into standard therapy for less than 6 months' duration to treat drug-susceptible, non-cavitary PTB. Non-inferiority was based on a 6% margin of difference. RESULTS: Of 4594 total participants in the three trials that met the inclusion criteria, 1066 patients had non-cavitary disease. The pooled difference in unfavorable outcomes was 5% (95%CI -3 to 13) in patients with non-cavitary disease treated with FQ-containing regimens vs. standard therapy. In subgroup analyses, the pooled difference in unfavorable outcomes was 1% (95%CI -3 to 5) when comparing the daily form of intervention regimen with standard therapy, and -1% (95%CI -5 to 4) between regimens replacing ethambutol (EMB) with an FQ and standard therapy. No difference in risk of adverse events was noted. CONCLUSION: Daily administered 4-month regimens with substitution of EMB by an FQ may be non-inferior to standard therapy in patients with culture-confirmed, non-cavitary, drug-susceptible PTB.

Xpert(®) MTB/RIF detection of rifampin resistance and time to treatment initiation in Harare, Zimbabwe.

BACKGROUND: Patients at elevated risk of drug-resistant tuberculosis (TB) are prioritized for Xpert(®) MTB/RIF testing; however, the clinical usefulness of the test in this population is understudied. DESIGN: From November 2011 to June 2014, consecutive out-patients with a history of previous TB in high-density suburbs of Harare, Zimbabwe, were tested using Xpert, solid and liquid culture, and the microscopic observation drug susceptibility assay. Diagnostic accuracy for rifampin (RMP) resistance and time to initiation of second-line regimens were ascertained. The rpoB gene was sequenced in cases with culture-confirmed RMP resistance and genotypic susceptibility. RESULTS: Among 352 retreatment patients, 71 (20%) were RMP-resistant, 98 (28%) RMP-susceptible, 64 (18%) culture-negative/Xpert-positive, and 119 (34%) culture-negative/Xpert-negative. Xpert had a sensitivity of 86% (95%CI 75-93) and a specificity of 98% (95%CI 92-100) for RMP-resistant TB. The positive predictive value of Xpert-determined RMP resistance for multidrug-resistant TB (MDR-TB) was 82% (95%CI 70-91). Of 71 (83%) participants, 59 initiated treatment with second-line drugs, with a median time to treatment initiation of 18 days (IQR 10-44). CONCLUSION: The diagnostic accuracy of Xpert for RMP resistance is high, although the predictive value for MDR-TB was lower than anticipated. Xpert allows for faster initiation of second-line treatment than culture-based drug susceptibility testing under programmatic conditions.

Factors Associated with Prevalent Tuberculosis Among Patients Receiving Highly Active Antiretroviral Therapy in a Nigerian Tertiary Hospital.

BACKGROUND: Tuberculosis (TB) causes significant morbidity/mortality among human immunodeficiency virus-infected individuals in Africa. Reducing TB burden in the era of highly active antiretroviral therapy (HAART) is a public health priority. AIM: We determined the factors associated with prevalent TB among patients receiving HAART. SUBJECTS AND METHODS: We conducted a cross-sectional study of adult patients who had received HAART for ≥12 weeks in a Nigerian tertiary hospital. Patients whose TB diagnosis predated HAART were excluded from the study. Pre-HAART data were collected from the clinic records, whereas post-HAART data were obtained through medical history, physical examination, and laboratory investigations. Standard TB screening/diagnostic algorithms as applicable in Nigeria were used. Logistic regression analysis was used to determine factors independently associated with prevalent TB. RESULTS: about 65.8% (222/339) were women. The mean age was 41.1 (10.0) years and 23.6% (73/339) had past history of TB. The prevalence of active TB was 7.7% (26/339). Among these patients, 42.3% (11/26) had pulmonary TB, 34.6% (9/26) had disseminated TB, whereas 23.1% (6/26) had only extra-pulmonary disease. Only 45% (9/20) of patients with pulmonary involvement had positive sputum smear. Factors independently associated with prevalent TB were lower social class (adjusted odds ratio [aOR]: 31.7; 95% confidence interval [CI]: 1.1-1417.3), HAART non-adherence (aOR125.5; 95% CI: 9.6-1636.3), baseline CD4 <200cells/µl (aOR31.0; 95%CI: 1.6-590.6), previous TB (aOR13.8; 95% CI: 2.0-94.1), and current hemoglobin <10 g/dl (aOR10.3; 95% CI: 1.1-99.2). CONCLUSION: Factors associated with prevalent TB were a lower social class, HAART non-adherence, severe immunosuppression before HAART initiation, previous TB, and anemia post-HAART. TB case finding should be intensified in these high-risk groups.

Factors Associated with Prevalent Tuberculosis Among Patients Receiving Highly Active Antiretroviral Therapy in a Nigerian Tertiary Hospital

Background: Tuberculosis (TB) causes significant morbidity/mortality among human immunodeficiency virus­infected individuals in Africa. Reducing TB burden in the era of highly active antiretroviral therapy (HAART) is a public health priority.Aim: We determined the factors associated with prevalent TB among patients receiving HAART.Subjects and Methods: We conducted a cross­sectional study of adult patients who had received HAART for ≥12 weeks in a Nigerian tertiary hospital. Patients whose TB diagnosis predated HAART were excluded from the study. Pre­HAART data were collected from the clinic records, whereas post­HAART data were obtained through medical history, physical examination, and laboratinvestigations.StandardTBscreening/diagnostic algorithms as applicable in Nigeria were used. Logistic regression analysis was used to determine factors independently associated with prevalent TB.Results: about 65.8% (222/339) were women. The mean age was 41.1 (10.0) years and 23.6% (73/339) had past history of TB. The prevalence of active TB was 7.7% (26/339). Among these patients, 42.3% (11/26) had pulmonary TB, 34.6% (9/26) had disseminated TB, whereas 23.1% (6/26) had only extra­pulmonary disease. Only 45% (9/20) of patients with pulmonary involvement had positive sputum smear. Factors independently associated with prevalent TB were lower social class (adjusted odds ratio [aOR]: 31.7; 95% confidence interval [CI]: 1.1­1417.3), HAART non­adherence (aOR125.5; 95% CI: 9.6­1636.3), baseline CD4 <200cells/µl (aOR31.0; 95%CI: 1.6­590.6), previous TB (aOR13.8; 95% CI: 2.0­94.1), and current hemoglobin <10 g/dl (aOR10.3; 95% CI: 1.1­99.2).Conclusion: Factors associated with prevalent TB were a lower social class, HAART non­adherence, severe immunosuppression before HAART initiation, previous TB, and anemia post­HAART. TB case finding should be intensified in these high­risk groups

Reduced sensitivity of the QuantiFERON(®) test in diabetic patients with smear-negative tuberculosis.

SETTING: Immunosuppressive conditions have been associated with low sensitivity of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) for the diagnosis of tuberculosis (TB). However, no systematic analysis of patient and bacterial characteristics has been performed before. OBJECTIVE: To determine the sensitivity and the risk factors for false-negative QuantiFERON(®)-TB (QFT) assay and TST in TB patients. DESIGN: We performed a retrospective analysis of data collected in a community-based study of TB in San Francisco, CA, USA. We included 300 TB patients who underwent QFT and TST. RESULTS: The risk factors for false-negative QFT were human immunodeficiency virus infection and the use of QuantiFERON(®)-TB Gold. In patients with sputum smear-negative TB, diabetes mellitus (DM) was associated with false-negative QFT (OR 2.85, 95%CI 1.02-7.97, P = 0.045). TST sensitivity was higher than QFT sensitivity in DM patients (OR 9.46, 95%CI 2.53-35.3). CONCLUSIONS: In San Francisco, QFT sensitivity was lower than that of TST, especially in patients with DM. Stratified analysis by sputum smear results showed that this association was specific to smear-negative TB. In contrast, TST was not affected by the presence of DM.

Tuberculosis contact investigation in low- and middle-income countries: standardized definitions and indicators.

There is a need for better utilization of program data for global tuberculosis (TB) control. Significant information could be gained from data collected by TB programs that could supplement traditional sources of evidence and contribute to policy development. For this operational information to be useful, it must be collected in a uniform manner, using standardized definitions and approaches to evaluation. As an example of an approach to uniformity in generating useful program data, we present recommendations for the standardization of definitions and indicators for the investigation of contacts of persons with infectious TB in low- and middle-income countries.

Sublineages of lineage 4 (Euro-American) Mycobacterium tuberculosis differ in genotypic clustering.

SETTING: Mycobacterium tuberculosis is classified into six phylogenetic lineages, each of which can be divided into sublineages. Sublineages of the same lineage have phenotypic differences, including their capacity to cause disease (pathogenicity). OBJECTIVE: 1) To test the hypothesis that different sublineages of lineage 4, which causes most of the tuberculosis (TB) in the United States, have varying ability to cause secondary cases as determined by genotypic clustering, a proxy for pathogenicity; and 2) to determine if spoligotype and mycobacterial interspersed repetitive units (MIRU) typing could infer sublineage. DESIGN: We included TB cases caused by lineage 4 strains from our community-based study in San Francisco. Sublineage was determined by regions of difference. Genotypic clustering was determined by insertion sequence 6110 and polymorphic guanine-cytosine-rich sequence. Associations between sublineages and patient characteristics were evaluated with adjusted and unadjusted analyses. RESULTS: The most frequent sublineage was H37Rv-like. In the adjusted analysis, sublineage 183 was associated with clustering and homelessness. We found that strains from different sublineages had convergent spoligotype and MIRU types. CONCLUSIONS: Sublineage 183 is associated with genotypic clustering, evidence of its being more able to cause secondary cases than the other lineage 4 sublineages. This finding suggests that bacterial factors contribute to the pathogenesis of TB. Spoligotype and MIRU type cannot be used to infer sublineage.

Strain classification of Mycobacterium tuberculosis: congruence between large sequence polymorphisms and spoligotypes.

Spoligotyping is used in molecular epidemiological studies, and signature patterns have identified strain families. However, homoplasy occurs in the markers used for spoligotyping, which could lead to identical spoligotypes in phylogenetically unrelated strains. We determined the accuracy of strain classification based on spoligotyping using the six large sequence and single nucleotide polymorphisms-defined lineages as a gold standard. Of 919 Mycobacterium tuberculosis isolates, 870 (95%) were classified into a spoligotype family. Strains from a particular spoligotype family belonged to the same lineage. We did not find convergence to the same spoligotype. Spoligotype families appear to be sub-lineages within the main lineages.

Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review.

OBJECTIVE: To provide a descriptive synthesis of the evidence assessing the efficacy and safety of higher doses of rifampin (RMP) for the treatment of pulmonary tuberculosis (TB). METHODS: Systematic review of randomized controlled trials that evaluate a range of RMP doses, including doses higher than standard (>10 mg/kg or >600 mg), used as part of combination drug therapies for pulmonary TB. Two reviewers applied inclusion criteria, assessed trial quality and extracted data. Inclusion criteria were smear- or culture-confirmed pulmonary TB, and English and French language articles. Exclusion criteria were RMP monotherapy and smear-negative TB. Outcomes included were sputum culture conversion, treatment failure, recurrence and adverse events, including hepatotoxicity and flu-like syndrome. RESULTS: Of 14 trials (4256 participants) identified, 12 were conducted before 1980. Four trials were considered high quality according to published guidelines. Study characteristics, including history of prior TB treatment, dose of RMP, duration of treatment, timing of introduction of intervention treatment, concomitant drugs, and duration of follow-up, varied, making synthesis of efficacy data challenging. Several trials suggested an advantage in terms of likelihood of culture conversion among patients receiving at least 900 mg RMP. However, an increased incidence of flu-like syndrome was seen when RMP doses of 900 mg and higher were given intermittently. CONCLUSION: Historical trials suggest that higher than standard RMP dosing results in improved culture conversion rates. Phase 2 and 3 clinical trials evaluating higher doses of RMP and other rifamycins are needed to confirm efficacy and assure tolerability. Pharmacokinetic studies will be needed to inform the development of such trials.

Differences among sublineages of the East-Asian lineage of Mycobacterium tuberculosis in genotypic clustering.

SETTING: The East-Asian lineage of Mycobacterium tuberculosis is composed of five sublineages, and includes the strains from the Beijing spoligotype family. In some studies these strains were highly pathogenic, although other studies did not support this finding. OBJECTIVE: To determine if the sublineages of the East-Asian lineage of M. tuberculosis differ in their capacity to cause secondary cases, as assessed by genotypic clustering of isolates. DESIGN: In a population-based study of 545 patients with M. tuberculosis from the East-Asian lineage in San Francisco, we used DNA-based fingerprinting to identify genotypic clustering, which was compared among the different sublineages defined by large sequence polymorphism. RESULTS: Strains from sublineage 207 had the highest frequency of genotypic clustering. In the multivariate analysis, only patients born in the United States were associated with clustering. CONCLUSIONS: We found evidence in a univariate analysis that the different East-Asian sublineages of M. tuberculosis have different frequencies of genotypic clustering. The effect size for this difference was unchanged in multivariate analysis, although loss of observations due to missing data resulted in a non-significant P value. It is tantalizing to hypothesize that the different East-Asian sublineages may differ in their capacity to cause secondary cases.

Does bleach processing increase the accuracy of sputum smear microscopy for diagnosing pulmonary tuberculosis?

Bleach digestion of sputum prior to smear preparation has been reported to increase the yield of microscopy for diagnosing pulmonary tuberculosis, even in high-HIV-prevalence settings. To determine the diagnostic accuracy of bleach microscopy, we updated a systematic review published in 2006 and applied the Grading of Recommendations Assessment, Development, and Evaluation framework to rate the overall quality of the evidence. We searched multiple databases (as of January 2009) for primary studies in all languages comparing bleach and direct microscopy. We assessed study quality using a validated tool and heterogeneity by standard methods. We used hierarchical summary receiver operating characteristic (HSROC) analysis to calculate summary estimates of diagnostic accuracy and random-effects meta-analysis to pool sensitivity and specificity differences. Of 14 studies (11 papers) included, 9 evaluated bleach centrifugation and 5 evaluated bleach sedimentation. Overall, examination of bleach-processed versus direct smears led to small increases in sensitivity (for bleach centrifugation, 6% [95% confidence interval [CI] = 3 to 10%, P = 0.001]; for bleach sedimentation, 9% [95% CI = 4 to 14%, P = 0.001]) and small decreases in specificity (for bleach centrifugation, -3% [95% CI = -4% to -1%, P = 0.004]; for bleach sedimentation, -2% [95% CI = -5% to 0%, P = 0.05]). Similarly, analysis of HSROC curves suggested little or no improvement in diagnostic accuracy. The quality of evidence was rated very low for both bleach centrifugation and bleach sedimentation. This updated systematic review suggests that the benefits of bleach processing are less than those described previously. Further research should focus on alternative approaches to optimizing smear microscopy, such as light-emitting diode fluorescence microscopy and same-day sputum collection strategies.

Sensitivity and specificity of fluorescence microscopy for diagnosing pulmonary tuberculosis in a high HIV prevalence setting.

SETTING: Mulago Hospital, Kampala, Uganda. OBJECTIVE: To evaluate the diagnostic performance of fluorescence microscopy (FM) for diagnosing pulmonary tuberculosis (TB) in a high human immunodeficiency virus (HIV) prevalence setting. DESIGN: Consecutive in-patients with cough for >2 weeks submitted two sputum specimens for smear microscopy. Smears were examined by conventional light microscopy (CM) and FM. The performance of the two methods was compared using mycobacterial culture as a reference standard. RESULTS: A total of 426 patients (82% HIV-infected) were evaluated. FM identified 11% more smear-positive patients than CM (49% vs. 38%, P < 0.001). However, positive FM results were less likely than positive CM results to be confirmed by culture when smears were read as either 'scanty' (54% vs. 90%, P < 0.001) or 1+ (82% vs. 91%, P = 0.02). Compared to CM, the sensitivity of FM was higher (72% vs. 64%, P = 0.005), and the specificity lower (81% vs. 96%, P < 0.001). In receiver operating characteristic analysis, maximum area under the curve for FM was obtained at a threshold of >4 acid-fast bacilli/100 fields (sensitivity 68%, specificity 90%). CONCLUSION: Although FM increases the sensitivity of sputum smear microscopy, additional data on FM specificity and on the clinical consequences associated with false-positive FM results are needed to guide implementation of this technology in high HIV prevalence settings.

T-cell assay conversions and reversions among household contacts of tuberculosis patients in rural India.

BACKGROUND: Interferon-gamma assays (IGRAs) are alternatives to the tuberculin skin test (TST), but IGRA conversions and reversions are not well understood. In a pilot study, we determined conversions and reversions using QuantiFERON-TB Gold In-Tube((R)) (QFT) among household contacts of TB cases, and evaluated the effect of using various definitions and criteria for conversions. DESIGN: In a cohort of 250 contacts in India, 46% were TST-positive at baseline and 54% were QFT-positive. We re-tested this cohort after 12 months. Conversion rates were estimated using several definitions. RESULTS: Of the 250 contacts, 205 (82%) underwent repeat testing. Among 85 contacts with baseline TST-negative/QFT-negative results, TST conversion rates ranged between 7.5% and 13.8%, and QFT conversion rates ranged between 11.8% and 21.2%, depending on the definitions used. Among 109 contacts who were QFT-positive at baseline, seven (6.4%) had QFT reversions. QFT reversions were most likely when the baseline TST was negative and QFT results were just above the diagnostic cut-off. CONCLUSIONS: QFT conversions and reversions occurred among contacts of TB cases. Conversion rates seemed to vary, depending on the test and definitions used for conversions. These findings need to be verified in larger studies in various settings.

International standards for tuberculosis care: relevance and implications for laboratory professionals.

On World Tuberculosis (TB) Day 2006, the International Standards for Tuberculosis Care (ISTC) was officially released and widely endorsed by several agencies and organizations. The ISTC release was the culmination of a year long global effort to develop and set internationally acceptable, evidence-based standards for tuberculosis care. The ISTC describes a widely endorsed level of care that all practitioners, public and private, should seek to achieve in managing individuals who have or are suspected of having, TB and is intended to facilitate the effective engagement of all healthcare providers in delivering high quality care for patients of all ages, including those with smear-positive, smear-negative and extra-pulmonary TB, TB caused by drug-resistant Mycobacterium tuberculosis and TB/HIV coinfection. In this article, we present the ISTC, with a special focus on the diagnostic standards and describe their implications and relevance for laboratory professionals in India and worldwide. Laboratory professionals play a critical role in ensuring that all the standards are actually met by providing high quality laboratory services for smear microscopy, culture and drug susceptibility testing and other services such as testing for HIV infection. In fact, if the ISTC is widely followed, it can be expected that there will be a greater need and demand for quality assured laboratory services and this will have obvious implications for all laboratories in terms of work load, requirement for resources and trained personnel and organization of quality assurance systems.

Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review.

Current international tuberculosis (TB) guidelines recommend the microscopic examination of three sputum specimens for acid-fast bacilli in the evaluation of persons suspected of having pulmonary TB. We conducted a systematic review of studies that quantified the diagnostic yield of each of three sputum specimens. By searching multiple databases and sources, we identified a total of 37 eligible studies. The incremental yield in smear-positive results (in studies using all smear-positive cases as the denominator) and the increase in sensitivity (in studies that used all culture-positive cases as the denominator) of the third specimen were the main outcomes of interest. Although heterogeneity in study methods and results presented challenges for data synthesis, subgroup analyses suggest that the average incremental yield and/or the increase in sensitivity of examining a third specimen ranged between 2% and 5%. Reducing the recommended number of specimens examined from three to two (particularly to two specimens collected on the same day) could benefit TB control programs, and potentially increase case detection for several reasons. A number of operational research issues need to be addressed. Studies examining the most effective and efficient means to utilize current technologies for microscopic examination of sputum would be most useful if they followed an internationally coordinated and standardized approach, both to strengthen the country-specific evidence base and to permit comparison among studies.