Evaluation of the 2007 WHO guideline to improve the diagnosis of tuberculosis in ambulatory HIV-positive adults

Background

In 2007 WHO issued a guideline to improve the diagnosis of smear-negative and extrapulmonary tuberculosis (EPTB) in HIV-positive patients. This guideline relies heavily on the acceptance of HIV-testing and availability of chest X-rays.

Methods and Findings

Cohort study of TB suspects in four tuberculosis (TB) clinics in Phnom Penh, Cambodia. We assessed the operational performance of the guideline, the incremental yield of investigations, and the diagnostic accuracy for smear-negative tuberculosis in HIV-positive patients using culture positivity as reference standard. 1,147 (68.9%) of 1,665 TB suspects presented with unknown HIV status, 1,124 (98.0%) agreed to be tested, 79 (7.0%) were HIV-positive. Compliance with the guideline for chest X-rays and sputum culture requests was 97.1% and 98.3% respectively. Only 35 of 79 HIV-positive patients (44.3%) with a chest X-ray suggestive of TB started TB treatment within 10 days. 105 of 442 HIV-positive TB suspects started TB treatment (56.2% smear-negative pulmonary TB (PTB), 28.6% smear-positive PTB, 15.2% EPTB). The median time to TB treatment initiation was 5 days (IQR: 2–13 days), ranging from 2 days (IQR: 1–11.5 days) for EPTB, over 2.5 days (IQR: 1–4 days) for smear-positive PTB to 9 days (IQR: 3–17 days) for smear-negative PTB. Among the 34 smear-negative TB patients with a confirmed diagnosis, the incremental yield of chest X-ray, clinical suspicion or abdominal ultrasound, and culture was 41.2%, 17.6% and 41.2% respectively. The sensitivity and specificity of the algorithm to diagnose smear-negative TB in HIV-positive TB suspects was 58.8% (95%CI: 42.2%–73.6%) and 79.4% (95%CI: 74.8%–82.4%) respectively.

Conclusions

Pending point-of-care rapid diagnostic tests for TB disease, diagnostic algorithms are needed. The diagnostic accuracy of the 2007 WHO guideline to diagnose smear-negative TB is acceptable. There is, however, reluctance to comply with the guideline in terms of immediate treatment initiation.     

Impact of Xpert MTB/RIF Testing on Tuberculosis Management and Outcomes in Hospitalized Patients in Uganda

Rationale

The clinical impact of Xpert MTB/RIF for tuberculosis (TB) diagnosis in high HIV-prevalence settings is unknown.

Objective

To determine the diagnostic accuracy and impact of Xpert MTB/RIF among high-risk TB suspects.

Methods

We prospectively enrolled consecutive, hospitalized, Ugandan TB suspects in two phases: baseline phase in which Xpert MTB/RIF results were not reported to clinicians and an implementation phase in which results were reported. We determined the diagnostic accuracy of Xpert MTB/RIF in reference to culture (solid and liquid) and compared patient outcomes by study phase.

Results

477 patients were included (baseline phase 287, implementation phase 190). Xpert MTB/RIF had high sensitivity (187/237, 79%, 95% CI: 73–84%) and specificity (190/199, 96%, 95% CI: 92–98%) for culture-positive TB overall, but sensitivity was lower (34/81, 42%, 95% CI: 31–54%) among smear-negative TB cases. Xpert MTB/RIF reduced median days-to-TB detection for all TB cases (1 [IQR 0–26] vs. 0 [IQR 0–1], p<0.001), and for smear-negative TB (35 [IQR 22–55] vs. 22 [IQR 0–33], p = 0.001). However, median days-to-TB treatment was similar for all TB cases (1 [IQR 0–5] vs. 0 [IQR 0–2], p = 0.06) and for smear-negative TB (7 [IQR 3–53] vs. 6 [IQR 1–61], p = 0.78). Two-month mortality was also similar between study phases among 252 TB cases (17% vs. 14%, difference +3%, 95% CI: −21% to +27%, p = 0.80), and among 87 smear-negative TB cases (28% vs. 22%, difference +6%, 95% CI: −34 to +46%, p = 0.77).

Conclusions

Xpert MTB/RIF facilitated more accurate and earlier TB diagnosis, leading to a higher proportion of TB suspects with a confirmed TB diagnosis prior to hospital discharge in a high HIV/low MDR TB prevalence setting. However, our study did not detect a decrease in two-month mortality following implementation of Xpert MTB/RIF possibly because of insufficient powering, differences in empiric TB treatment rates, and disease severity between study phases.     

Microscopic-Observation Drug-Susceptibility Assay for the Diagnosis of Drug-Resistant Tuberculosis in Harare,Zimbabwe

Introduction

Limited data exist on use of the microscopic-observation drug-susceptibility (MODS) assay among persons suspected of MDR-TB living in high HIV-prevalence settings.

Methods

We retrospectively reviewed available clinical and drug susceptibility data for drug-resistant TB suspects referred for culture and drug-susceptibility testing between April 1, 2011 and March 1, 2012. The diagnostic accuracy of MODS was estimated against a reference standard including Löwenstein-Jensen (LJ) media and manual liquid (BACTEC MGIT) culture. The accuracy of MODS drug-susceptibility testing (DST) was assessed against a reference standard absolute concentration method.

Results

One hundred thirty-eight sputum samples were collected from 99 drug-resistant TB suspects; in addition, six previously cultured MDR isolates were included for assessment of DST accuracy. Among persons with known HIV infection status, 39/59 (66%) were HIV-infected. Eighty-six percent of patients had a history of prior TB treatment, and 80% of individuals were on antituberculous treatment at the time of sample collection. M. tuberculosis was identified by reference standard culture among 34/98 (35%) MDR-TB suspects. Overall MODS sensitivity for M. tuberculosis detection was 85% (95% CI, 69–95%) and specificity was 93% (95% CI, 84–98%); diagnostic accuracy did not significantly differ by HIV infection status. Median time to positivity was significantly shorter for MODS (7 days; IQR 7–15 days) than MGIT (12 days; IQR 6–16 days) or LJ (28 days; IQR 21–35 days; p<0.001). Of 33 specimens with concurrent DST results, sensitivity of the MODS assay for detection of resistance to isoniazid, rifampin, and MDR-TB was 88% (95% CI, 68–97%), 96% (95% CI, 79–100%), and 91% (95% CI, 72–99%), respectively; specificity was 89% (95% CI, 52–100%), 89% (95% CI, 52–100%), and 90% (95% CI, 56–100%), respectively.

Conclusion

In a high HIV-prevalence setting, MODS diagnosed TB and drug-resistant TB with high sensitivity and shorter turnaround time compared with standard culture and DST methods.     

Performance of the 2007 WHO Algorithm to Diagnose Smear-Negative Pulmonary Tuberculosis in a HIV Prevalent Setting

Background

The 2007 WHO algorithm for diagnosis of smear-negative pulmonary tuberculosis (PTB) including Mycobacterium tuberculosis (MTB) culture was evaluated in a HIV prevalent area of Kenya.

Methods

PTB smear-negative adult suspects were included in a prospective diagnostic study (2009–2011). In addition, program data (2008–2009) were retrospectively analysed. At the first consultation, clinical examination, chest X-ray, and sputum culture (Thin-Layer-Agar and Lowenstein-Jensen) were performed. Patients not started on TB treatment were clinically re-assessed after antibiotic course. The algorithm performance was calculated using culture as reference standard.

Results

380 patients were included prospectively and 406 analyzed retrospectively. Culture was positive for MTB in 17.5% (61/348) and 21.8% (72/330) of cases. Sensitivity of the clinical-radiological algorithm was 55.0% and 31.9% in the prospective study and the program data analysis, respectively. Specificity, positive and negative predictive values were 72.9%, 29.7% and 88.6% in the prospective study and 79.8%, 30.7% and 80.8% in the program data analysis. Performing culture increased the number of confirmed TB patients started on treatment by 43.3% in the prospective study and by 44.4% in the program data analysis. Median time to treatment of confirmed TB patients was 6 days in the prospective study and 27 days in the retrospective study. Inter-reader agreement for X-ray interpretation between the study clinician and a radiologist was low (Kappa coefficient = 0.11, 95%CI: 0.09–0.12). In a multivariate logistic analysis, past TB history, number of symptoms and signs at the clinical exam were independently associated with risk of overtreatment.

Conclusion

The clinical-radiological algorithm is suboptimal to diagnose smear-negative PTB. Culture increases significantly the proportion of confirmed TB cases started on treatment. Better access to rapid MTB culture and development of new diagnostic tests is necessary.     

Impact and Cost-Effectiveness of Culture for Diagnosis of Tuberculosis in HIV-Infected Brazilian Adults

Background

Culture of Mycobacterium tuberculosis currently represents the closest “gold standard” for diagnosis of tuberculosis (TB), but operational data are scant on the impact and cost-effectiveness of TB culture for human immunodeficiency (HIV-) infected individuals in resource-limited settings.

Methodology/Principal Findings

We recorded costs, laboratory results, and dates of initiating TB therapy in a centralized TB culture program for HIV-infected patients in Rio de Janeiro, Brazil, constructing a decision-analysis model to estimate the incremental cost-effectiveness of TB culture from the perspective of a public-sector TB control program. Of 217 TB suspects presenting between January 2006 and March 2008, 33 (15%) had culture-confirmed active tuberculosis; 23 (70%) were smear-negative. Among smear-negative, culture-positive patients, 6 (26%) began TB therapy before culture results were available, 11 (48%) began TB therapy after culture result availability, and 6 (26%) did not begin TB therapy within 180 days of presentation. The cost per negative culture was US$17.52 (solid media)–$23.50 (liquid media). Per 1,000 TB suspects and compared with smear alone, TB culture with solid media would avert an estimated eight TB deaths (95% simulation interval [SI]: 4, 15) and 37 disability-adjusted life years (DALYs) (95% SI: 13, 76), at a cost of $36 (95% SI: $25, $50) per TB suspect or $962 (95% SI: $469, $2642) per DALY averted. Replacing solid media with automated liquid culture would avert one further death (95% SI: −1, 4) and eight DALYs (95% SI: −4, 23) at $2751 per DALY (95% SI: $680, dominated). The cost-effectiveness of TB culture was more sensitive to characteristics of the existing TB diagnostic system than to the accuracy or cost of TB culture.

Conclusions/Significance

TB culture is potentially effective and cost-effective for HIV-positive patients in resource-constrained settings. Reliable transmission of culture results to patients and integration with existing systems are essential.     

A Diagnostic Accuracy Study of Xpert?MTB/RIF in HIV-Positive Patients with High Clinical Suspicion of Pulmonary Tuberculosis in Lima,Peru

Background

Diagnosis of pulmonary tuberculosis (TB) among human immunodeficiency virus (HIV) patients remains complex and demands easy to perform and accurate tests. Xpert®MTB/RIF (MTB/RIF) is a molecular TB diagnostic test which is rapid and convenient; the test requires minimal human resources and reports results within two hours. The majority of performance studies of MTB/RIF have been performed in high HIV burden settings, thus TB diagnostic studies among HIV patients in low HIV prevalence settings such as Peru are still needed.

Methodology/Principal Findings

From April 2010 to May 2011, HIV-positive patients with high clinical suspicion of TB were enrolled from two tertiary hospitals in Lima, Peru. Detection of TB by MTB/RIF was compared to a composite reference standard Löwenstein-Jensen (LJ) and liquid culture. Detection of rifampicin resistance was compared to the LJ proportion method. We included 131 patients, the median CD4 cell count was 154.5 cells/mm³ and 45 (34.4%) had TB. For TB detection among HIV patients, sensitivity of MTB/RIF was 97.8% (95% CI 88.4–99.6) (44/45); specificity was 97.7% (95% CI 91.9–99.4) (84/86); the positive predictive value was 95.7% (95% CI 85.5–98.8) (44/46); and the negative predictive value, 98.8% (95% CI 93.6–99.8) (84/85). MTB/RIF detected 13/14 smear-negative TB cases, outperforming smear microscopy [97.8% (44/45) vs. 68.9% (31/45); p = 0.0002]. For rifampicin resistance detection, sensitivity of MTB/RIF was 100% (95% CI 61.0–100.0) (6/6); specificity was 91.0% (95% CI 76.4–96.9) (30/33); the positive predictive value was 66.7% (95% CI 35.4–87.9) (6/9); and the negative predictive value was 100% (95% CI 88.7 –100.0) (30/30).

Conclusions/Significance

In HIV patients in our population with a high clinical suspicion of TB, MTB/RIF performed well for TB diagnosis and outperformed smear microscopy.     

Diagnostic Value of the Amplicor PCR Assay for Initial Diagnosis and Assessment of Treatment Response for Pulmonary Tuberculosis

We evaluated the Amplicor PCR assay as an initial diagnostic tool on the basis of clinical diagnosis, and assessed this assay as a follow-up test for patients with pulmonary tuberculosis during chemotherapy. Of the 208 specimens from 155 patients who were bacteriologically and/or clinically diagnosed with active tuberculosis before chemotherapy, 144 were Amplicor PCR-positive (sensitivity, 69.2%), which was equal to the results of culturing. Among 89 specimens which showed positive results by smear and culturing, the Amplicor PCR assay detected 87 (97.8%), whereas among 55 specimens which showed smear-negative but culture-positive results, the Amplicor PCR assay detected 46 (83.6%)(P = 0.003). No false positive results were found in the two systems (specificity, 100%, 120/120). The Amplicor PCR assay was also evaluated as a follow-up test using 926 specimens from 207 patients receiving active tuberculosis chemotherapy. Among 433 specimens which showed Amplicor-PCR positive, 222 (51.3%) were culture-negative. On the other hand, among 233 culture-positive specimens, only 12 (5.2%) were Amplicor PCR-negative. Therefore, this assay is useful for the rapid diagnosis of tuberculosis. The duration of Amplicor PCR-positive after culture-negative conversion was significantly associated with the presence of cavitary lesion, smear-positive specimens before treatment, and smear-positive specimens with negative cultures during chemotherapy.     

Association between ACE I/D polymorphism and pulmonary tuberculosis in Chinese population

Tuberculosis (TB) remains a global public health problem worldwide. The objective of the current study is to investigate the possible association of ACE I/D polymorphism with pulmonary TB (PTB) for Chinese in Sichuan province. Three hundred eighty-six PTB patients and 398 healthy controls were genotyped to analyze the I/D polymorphism using PCR method. The results showed that the I/D polymorphism was not associated with susceptibility to PTB for Chinese (D vs. I: OR 1.03, 95 % CI 0.84–1.26, and P = 0.77; DD vs. II+DI: OR 1.09, 95 % CI 0.73–1.63, and P = 0.68; DD+DI vs. II: OR 1.00, 95 % CI 0.74–1.33, and P = 0.98). The I/D polymorphism in the ACE gene may not a risk factor for PTB in Chinese.     

Early and Efficient Detection of Mycobacterium tuberculosis in Sputum by Microscopic Observation of Broth Cultures

Early, efficient and inexpensive methods for the detection of pulmonary tuberculosis are urgently needed for effective patient management as well as to interrupt transmission. These methods to detect M. tuberculosis in a timely and affordable way are not yet widely available in resource-limited settings. In a developing-country setting, we prospectively evaluated two methods for culturing and detecting M. tuberculosis in sputum. Sputum samples were cultured in liquid assay (micro broth culture) in microplate wells and growth was detected by microscopic observation, or in Löwenstein–Jensen (LJ) solid media where growth was detected by visual inspection for colonies. Sputum samples were collected from 321 tuberculosis (TB) suspects attending Bugando Medical Centre, in Mwanza, Tanzania, and were cultured in parallel. Pulmonary tuberculosis cases were diagnosed using the American Thoracic Society diagnostic standards. There were a total of 200 (62.3%) pulmonary tuberculosis cases. Liquid assay with microscopic detection detected a significantly higher proportion of cases than LJ solid culture: 89.0% (95% confidence interval [CI], 84.7% to 93.3%) versus 77.0% (95% CI, 71.2% to 82.8%) (p = 0.0007). The median turn around time to diagnose tuberculosis was significantly shorter for micro broth culture than for the LJ solid culture, 9 days (interquartile range [IQR] 7–13), versus 21 days (IQR 14–28) (p<0.0001). The cost for micro broth culture (labor inclusive) in our study was US $4.56 per sample, versus US $11.35 per sample for the LJ solid culture. The liquid assay (micro broth culture) is an early, feasible, and inexpensive method for detection of pulmonary tuberculosis in resource limited settings.     

Development of a Simple Reliable Radiographic Scoring System to Aid the Diagnosis of Pulmonary Tuberculosis

Rationale

Chest radiography is sometimes the only method available for investigating patients with possible pulmonary tuberculosis (PTB) with negative sputum smears. However, interpretation of chest radiographs in this context lacks specificity for PTB, is subjective and is neither standardized nor reproducible. Efforts to improve the interpretation of chest radiography are warranted.

Objectives

To develop a scoring system to aid the diagnosis of PTB, using features recorded with the Chest Radiograph Reading and Recording System (CRRS).

Methods

Chest radiographs of outpatients with possible PTB, recruited over 3 years at clinics in South Africa were read by two independent readers using the CRRS method. Multivariate analysis was used to identify features significantly associated with culture-positive PTB. These were weighted and used to generate a score.

Results

473 patients were included in the analysis. Large upper lobe opacities, cavities, unilateral pleural effusion and adenopathy were significantly associated with PTB, had high inter-reader reliability, and received 2, 2, 1 and 2 points, respectively in the final score. Using a cut-off of 2, scores below this threshold had a high negative predictive value (91.5%, 95%CI 87.1,94.7), but low positive predictive value (49.4%, 95%CI 42.9,55.9). Among the 382 TB suspects with negative sputum smears, 229 patients had scores <2; the score correctly ruled out active PTB in 214 of these patients (NPV 93.4%; 95%CI 89.4,96.3). The score had a suboptimal negative predictive value in HIV-infected patients (NPV 86.4, 95% CI 75,94).

Conclusions

The proposed scoring system is simple, and reliably ruled out active PTB in smear-negative HIV-uninfected patients, thus potentially reducing the need for further tests in high burden settings. Validation studies are now required.     

A multi-center study to evaluate the performance of phage amplified biologically assay for detecting TB in sputum in the pulmonary TB patients

Objective

To evaluate the performance of phage amplified biologically assay (PhaB) for detecting tuberculosis (TB) in sputum in the pulmonary tuberculosis (PTB) patients.

Methods

Shanghai Tuberculosis Key Laboratory of Shanghai Pulmonary Hospital participated in the project in collaboration with the laboratories of six hospitals and a total of 1660 eligible participants (1351 PTB patients and 309 non-TB patients) were included in the study. The sputum samples from the participants were detected by smear microscopy, PhaB, and Löwenstein-Jensen (L-J) culture method, respectively.

Results

The overall sensitivity of PhaB were higher than that of L-J culture and smear microscopy (p<0.05). The sensitivity of PhaB for detecting smear-negative specimens was obviously higher than that of L-J culture (p<0.05). Compared with L-J culture, the overall sensitivity, specificity, PPV, NPV, ACC and Kappa value of PhaB were 98.4 (95% Cl: 96.9–99.3), 71.6 (95% Cl: 68.4–74.6), 67.7, 98.7, 81.7% and 0.643, respectively. The detection median time of PhaB only needed 48 hours, which was significantly less than that (31 days) of L-J culture method.

Conclusion

PhaB method is a rapid and sensitive method for detecting TB in sputum in PTB patients; especially for the diagnosis of smear-negative PTB, PhaB method is obviously more sensitive than L-J culture method.     

Smear positive pulmonary tuberculosis and associated factors among homeless individuals in Dessie and Debre Birhan towns,Northeast Ethiopia

Background

Tuberculosis (TB) remains one of the globe’s deadliest communicable diseases. The homeless individuals are at high risk to acquire TB and multi-drug resistant TB (MDR-TB), because of their poor living conditions and risky behaviors. Tuberculosis and MDR-TB in the homeless individuals can pose a risk to entire communities. However, the magnitude of the problem is not known in Ethiopia. Therefore, the aim of this study was to determine the prevalence and associated factors of smear positive pulmonary TB (PTB) and MDR-TB among homeless individuals in Dessie and Debre Birhan towns, Northeast Ethiopia.

Methods

A community based cross-sectional study design was conducted from September 2014 to June 2015. Using an active screening with cough of ≥2 weeks, 351 TB suspects homeless individuals were participated in this study. Data were collected by using pre-tested and structured questionnaire. Spot-morning-spot sputum sample was collected and examined for acid-fast bacilli (AFB) using fluorescence microscopy by Auramine O staining technique. All AFB positive sputum was further analyzed by GeneXpert for detection of Mycobacterium tuberculosis complex and rifampicin resistant gene. Univariate and multivariate logistic regressions were applied to identify factors associated with smear positive PTB and P value <0.05 was considered as statistically significant.

Results

The prevalence of smear positive PTB was 2.6 % (95 % CI 1.3–5) among TB suspect homeless individuals. Extrapolation of this study finding implies that there were 505 smear positive PTB per 100,000 homeless individuals. All smear positive PTB sputum specimens were further analyzed by GeneXpert assay, the assay confirmed that all were positive for MTBC but none were resistant to RIF or MDR. Smoking cigarette regularly for greater than 5 years (AOR 10.1, 95 % CI 1.1, 97.7), body mass index lower than 18.5 (AOR 6.9, 95 % CI 1.12, 41.1) and HIV infection (AOR 6.8, 95 % CI 1.1, 40.1) were significantly associated with smear positive PTB.

Conclusion

The prevalence of smear positive PTB among TB suspect homeless individuals was 2.6 %. Among smear positive PTB, prevalence of HIV co-infection was very high 5 (55.5 %). Smoking cigarette regularly for greater than 5 years, BMI lower than 18.5 and HIV infection were factors associated with smear positive PTB. Special emphasis is needed for homeless individuals to exert intensive effort to identify undetected TB cases to limit the circulation of the disease into the community.

     

Prevalence and Risk Factors for Adult Pulmonary Tuberculosis in a Metropolitan City of South India

Background

The present study measured the community prevalence and risk factors of adult pulmonary tuberculosis (PTB) in Chennai city, and also studied geographical distribution and the presence of different M. tuberculosis strains in the survey area.

Methods

A community-based cross sectional survey was carried out from July 2010 to October 2012 in Chennai city. Prevalence of bacteriologically positive PTB was estimated by direct standardization method. Univariate and multivariate analyses were carried out to identify significant risk factors. Drug susceptibility testing and spoligotyping was performed on isolated M. tuberculosis strains. Mapping of PTB cases was done using geographic positioning systems.

Results

Of 59,957 eligible people, 55,617 were screened by X-ray and /or TB symptoms and the prevalence of smear, culture, and bacteriologically positive PTB was estimated to be 228 (95% CI 189–265), 259 (95% CI 217–299) and 349 (95% CI 330–428) per 100,000 population, respectively. Prevalence of smear, culture, and bacteriologically positive PTB was highest amongst men aged 55–64 years. Multivariate analysis showed that occurrence of both culture and bacteriologically positive PTB disease was significantly associated with: age >35 years, past history of TB treatment, BMI <18.5 Kgs/m², solid cooking fuel, and being a male currently consuming alcohol. The most frequent spoligotype family was East African Indian. Spatial distribution showed that a high proportion of patients were clustered in the densely populated north eastern part of the city.

Conclusion

Our findings demonstrate that TB is a major public health problem in this urban area of south India, and support the use of intensified case finding in high risk groups. Undernutrition, slum dwelling, indoor air pollution and alcohol intake are modifiable risk factors for TB disease.     

Comparing Tuberculosis Diagnostic Yield in Smear/Culture and Xpert? MTB/RIF-Based Algorithms Using a Non-Randomised Stepped-Wedge Design

Setting

Primary health services in Cape Town, South Africa.

Study Aim

To compare tuberculosis (TB) diagnostic yield in an existing smear/culture-based and a newly introduced Xpert^® MTB/RIF-based algorithm.

Methods

TB diagnostic yield (the proportion of presumptive TB cases with a laboratory diagnosis of TB) was assessed using a non-randomised stepped-wedge design as sites transitioned to the Xpert^® based algorithm. We identified the full sequence of sputum tests recorded in the electronic laboratory database for presumptive TB cases from 60 primary health sites during seven one-month time-points, six months apart. Differences in TB yield and temporal trends were estimated using a binomial regression model.

Results

TB yield was 20.9% (95% CI 19.9% to 22.0%) in the smear/culture-based algorithm compared to 17.9% (95%CI 16.4% to 19.5%) in the Xpert^® based algorithm. There was a decline in TB yield over time with a mean risk difference of -0.9% (95% CI -1.2% to -0.6%) (p<0.001) per time-point. When estimates were adjusted for the temporal trend, TB yield was 19.1% (95% CI 17.6% to 20.5%) in the smear/culture-based algorithm compared to 19.3% (95% CI 17.7% to 20.9%) in the Xpert^® based algorithm with a risk difference of 0.3% (95% CI -1.8% to 2.3%) (p = 0.796). Culture tests were undertaken for 35.5% of smear-negative compared to 17.9% of Xpert^® negative low MDR-TB risk cases and for 82.6% of smear-negative compared to 40.5% of Xpert^® negative high MDR-TB risk cases in respective algorithms.

Conclusion

Introduction of an Xpert^® based algorithm did not produce the expected increase in TB diagnostic yield. Studies are required to assess whether improving adherence to the Xpert^® negative algorithm for HIV-infected individuals will increase yield. In light of the high cost of Xpert^®, a review of its role as a screening test for all presumptive TB cases may be warranted.     

Liquid vs Solid Culture Medium to Evaluate Proportion and Time to Change in Management of Suspects of Tuberculosis—A Pragmatic Randomized Trial in Secondary and Tertiary Health Care Units in Brazil

Background

The use of liquid medium (MGIT960) for tuberculosis (TB) diagnosis was recommended by WHO in 2007. However, there has been no evaluation of its effectiveness on clinically important outcomes.

Methods and Findings

A pragmatic trial was carried out in a tertiary hospital and a secondary health care unit in Rio de Janeiro City, Brazil. Participants were 16 years or older, suspected of having TB. They were excluded if only cerebral spinal fluid or blood specimens were available for analysis. MGIT960 technique was compared with the Lowenstein-Jensen (LJ) method for laboratory diagnosis of active TB. Primary outcome was the proportion of patients who had their initial medical management changed within 2 months after randomisation. Secondary outcomes were: mean time for changing the procedure, patient satisfaction with the overall treatment and adverse events. Data were analysed by intention-to-treat. Between April 2008 and September 2011, 693 patients were enrolled (348 to MGIT, 345 to LJ). Smear and culture results were positive for 10% and 15.7% of participants, respectively. Patients in the MGIT arm had their initial medical management changed more frequently than those in the LJ group (10.1% MGIT vs 3.8% LJ, RR 2.67 95% CI 1.44–.96, p = 0.002, NNT 16, 95% CI 10–39). Mean time for changing the initial procedure was greater in LJ group at both sites: 20.0 and 29.6 days in MGIT group and 52.2 and 64.3 in LJ group (MD 33.5, 95% CI 30.6–36.4, p = 0.0001). No other important differences were observed.

Conclusions

This study suggests that opting for the MGIT960 system for TB diagnosis provides a promising case management model for improving the quality of care and control of TB.

Trial Registration

Controlled-Trials.com ISRCTN79888843     

Investigation outcomes of tuberculosis suspects in the health centers of Addis Ababa, Ethiopia

Background

Little is known about the prevalence of tuberculosis (TB) and HIV among TB suspects in primary health care units in Ethiopia.

Methods

In the period of February to March, 2009, a cross sectional survey was done in 27 health centers of Addis Ababa to assess the prevalence of TB and HIV among TB suspects who have > = 2 weeks symptoms of TB such as cough, fever and weight loss. Diagnosis of TB and HIV was based on the national guidelines. Information concerning socio-demographic variables and knowledge of the respondents about TB was collected using pretested questionnaire.

Results

Of the 545 TB suspects, 506 (92.7%) of them participated in the study. The prevalence of both pulmonary and extra pulmonary TB was 46.0% (233/506). The smear positivity rate among pulmonary TB suspect was 21.3%. Of the TB suspects, 298 (58.9%) of them were tested for HIV and 27.2% (81/298) were HIV seropositive. Fifty percent of the HIV positive TB suspects had TB. TB suspects who had a contact history with a TB patient in the family were 9 times more likely to have TB than those who did not have a contact history, [OR = 9.1, (95%CI:4.0, 20.5)]. Individuals who had poor [OR = 5.2, (95%CI: 2.3, 11.2)] and fair knowledge [OR = 3.7, (95%CI: 1.3, 10.4)] about TB were more likely to have TB than individuals who had good knowledge.

Conclusion

In conclusion, the prevalence of TB among TB suspects with duration of 2 or more weeks is high. Fifty percent of the HIV positive TB suspects had TB. Case finding among TB suspects with duration of 2 or more weeks should be intensified particularly among those who have a contact history with a TB patient.     

Survival among Patients with HIV Infection and Smear-Negative Pulmonary Tuberculosis - United States, 1993–2006

Background

In patients with HIV and tuberculosis (TB) in resource-constrained settings, smear-negative disease has been associated with higher mortality than smear-positive disease. Higher reported mortality may be due to misdiagnosis, diagnostic delays, or because smear-negative disease indicates more advanced immune suppression.

Methods

We analyzed culture-confirmed, pulmonary TB among patients with TB and HIV in the United States from 1993–2008 to calculate prevalence ratios (PRs) for smear-negative disease by demographic and clinical characteristics. Allowing two years for treatment outcome to be reported, we determined hazard ratios (HRs) for survival by smear status, adjusted for significant covariates on patients before 2006.

Results

Among 16,710 cases with sputum smear results, 6,739 (39%) were sputum smear-negative and 9,971 (58%) were sputum smear-positive. The prevalence of smear-negative disease was lower in male patients (PR: 0.89, 95% confidence interval [CI]: 0.86–0.93) and in those who were homeless (PR: 0.92, CI: 0.87–0.97) or used alcohol excessively (PR: 0.91, CI: 0.87–0.95), and higher in persons diagnosed while incarcerated (PR: 1.20, CI: 1.13–1.27). Patients with smear-negative disease had better survival compared to patients with smear-positive disease, both before (HR: 0.82, CI: 0.75–0.90) and after (HR: 0.81, CI: 0.71–0.92) the introduction of combination anti-retroviral therapy.

Conclusions

In the United States, smear-negative pulmonary TB in patients with HIV was not associated with higher mortality, in contrast to what has been documented in high TB burden settings. Smear-negative TB can be routinely and definitively diagnosed in the United States, whereas high-burden countries often rely solely on AFB-smear microscopy. This difference could contribute to diagnostic and treatment delays in high-burden countries, possibly resulting in higher mortality.     

Risk Factors for Inadequate TB Case Finding in Rural Western Kenya: A Comparison of Actively and Passively Identified TB Patients

Background

The findings of a prevalence survey conducted in western Kenya, in a population with 14.9% HIV prevalence suggested inadequate case finding. We found a high burden of infectious and largely undiagnosed pulmonary tuberculosis (PTB), that a quarter of the prevalent cases had not yet sought care, and a low case detection rate.

Objective and methods

We aimed to identify factors associated with inadequate case finding among adults with PTB in this population by comparing characteristics of 194 PTB patients diagnosed in a health facility after self-report, i.e., through passive case detection, with 88 patients identified through active case detection during the prevalence survey. We examined associations between method of case detection and patient characteristics, including HIV-status, socio-demographic variables and disease severity in univariable and multivariable logistic regression analyses.

Findings

HIV-infection was associated with faster passive case detection in univariable analysis (crude OR 3.5, 95% confidence interval (CI) 2.0–5.9), but in multivariable logistic regression this was largely explained by the presence of cough, illness and clinically diagnosed smear-negative TB (adjusted OR (aOR) HIV 1.8, 95% CI 0.85–3.7). Among the HIV-uninfected passive case detection was less successful in older patients aOR 0.76, 95%CI 0.60–0.97 per 10 years increase), and women (aOR 0.27, 95%CI 0.10–0.73). Reported current or past alcohol use reduced passive case detection in both groups (0.42, 95% CI 0.23–0.79). Among smear-positive patients median durations of cough were 4.0 and 6.9 months in HIV-infected and uninfected patients, respectively.

Conclusion

HIV-uninfected patients with infectious TB who were older, female, relatively less ill, or had a cough of a shorter duration were less likely found through passive case detection. In addition to intensified case finding in HIV-infected persons, increasing the suspicion of TB among HIV-uninfected women and the elderly are needed to improve TB case detection in Kenya.     

Trends of Tuberculosis Case Notification and Treatment Outcomes in the Sidama Zone,Southern Ethiopia: Ten-Year Retrospective Trend Analysis in Urban-Rural Settings

BackgroundEthiopia is one of the high tuberculosis (TB) burden countries. An analysis of trends and differentials in case notifications and treatment outcomes of TB may help improve our understanding of the performance of TB control services.MethodsA retrospective trend analysis of TB cases was conducted in the Sidama Zone in southern Ethiopia. We registered all TB cases diagnosed and treated during 2003–2012 from all health facilities in the Sidama Zone, and analysed trends of TB case notification rates and treatment outcomes.ResultsThe smear positive (PTB+) case notification rate (CNR) increased from 55 (95% CI 52.5–58.4) to 111 (95% CI 107.4–114.4) per 10⁵ people. The CNRs of PTB+ in people older than 45 years increased by fourfold, while the mortality of cases during treatment declined from 11% to 3% for smear negative (PTB-) (X²_trend, P<0.001) and from 5% to 2% for PTB+ (X²_trend, P<0.001). The treatment success was higher in rural areas (AOR 1.11; CI 95%: 1.03–1.2), less for PTB- (AOR 0.86; CI 95%: 0.80–0.92) and higher for extra-pulmonary TB (AOR 1.10; CI 95%: 1.02–1.19) compared to PTB+. A higher lost-to-follow up was observed in men (AOR 1.15; CI 95%: 1.06–1.24) and among PTB- cases (AOR 1.14; CI 95%: 1.03–1.25). More deaths occurred in PTB-cases (AOR 1.65; 95% CI: 1.44–1.90) and among cases older than 65 years (AOR 3.86; CI 95%: 2.94–5.10). Lastly, retreatment cases had a higher mortality than new cases (6% vs 3%).ConclusionOver the past decade TB CNRs and treatment outcomes improved, whereas the disparities of disease burden by gender and place of residence reduced and mortality declined. Strategies should be devised to address higher risk groups for poor treatment outcomes.     

Impact of Community-Based DOT on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis

Background

Poor adherence to tuberculosis (TB) treatment can lead to prolonged infectivity and poor treatment outcomes. Directly observed treatment (DOT) seeks to improve adherence to TB treatment by observing patients while they take their anti-TB medication. Although community-based DOT (CB-DOT) programs have been widely studied and promoted, their effectiveness has been inconsistent. The aim of this study was to critical appraise and summarize evidence of the effects of CB-DOT on TB treatment outcomes.

Methods

Studies published up to the end of February 2015 were identified from three major international literature databases: Medline/PubMed, EBSCO, and EMBASE. Unpublished data from the grey literature were identified through Google and Google Scholar searches.

Results

Seventeen studies involving 12,839 pulmonary TB patients (PTB) in eight randomized controlled trials (RCTs) and nine cohort studies from 12 countries met the criteria for inclusion in this review and 14 studies were included in meta-analysis. Compared with clinic-based DOT, pooled results of RCTs for all PTB cases (including smear-negative or -positive, new or retreated TB cases) and smear-positive PTB cases indicated that CB-DOT promoted successful treatment [pooled RRs (95%CIs): 1.11 (1.02–1.19) for all PTB cases and 1.11 (1.02–1.19) for smear-positive PTB cases], and completed treatment [pooled RRs (95%CIs): 1.74(1.05, 2.90) for all PTB cases and 2.22(1.16, 4.23) for smear-positive PTB cases], reduced death [pooled RRs (95%CIs): 0.44 (0.26–0.72) for all PTB cases and 0.39 (0.23–0.66) for smear-positive PTB cases], and transfer out [pooled RRs (95%CIs): 0.37 (0.23–0.61) for all PTB cases and 0.42 (0.25–0.70) for smear-positive PTB cases]. Pooled results of all studies (RCTs and cohort studies) with all PTB cases demonstrated that CB-DOT promoted successful treatment [pooled RR (95%CI): 1.13 (1.03–1.24)] and curative treatment [pooled RR (95%CI): 1.24 (1.04–1.48)] compared with self-administered treatment.

Conclusions

CB-DOT did improved TB treatment outcomes according to the pooled results of included studies in this review. Studies on strategies for implementation of patient-centered and community-centered CB-DOT deserve further attention.