Electronic tuberculosis surveillance systems: a tool for managing today's TB programs.

The World Health Organization (WHO) released the Stop TB Strategy in 2006, along with a revised version of the tuberculosis (TB) recording and reporting forms and register. These publications illustrate the need for an enhanced TB surveillance system that will include such key elements as rapid assessment of the quality of DOTS services; integration and response to the human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) epidemic; TB control challenges, such as increased smear-negative and extra-pulmonary TB and multidrug-resistant TB (MDR-TB); increased engagement of all care providers, such as private health care services and the community; and promotion of research to support program improvement. Electronic surveillance systems utilize computer technology to facilitate the capture, transfer and reporting of the WHO-recommended TB data elements. Electronic surveillance offers several potential advantages over the traditional paper-based systems used in many low-resource settings, such as improved data quality and completeness, more feasible links to other health care programs, quality-enhanced data entry and analysis features and increased data security. These advantages must, however, be weighed against the requirements and costs of electronic surveillance, including implementation and support of a quality paper-based surveillance system and the additional costs associated with infrastructure, training and human resources for the implementation and continuing support of an electronic system. Using examples from three different electronic TB surveillance systems that are being implemented in various resource-limited settings, this article demonstrates the feasibility, requirements and value of such systems to support the WHO-recommended enhancement of TB surveillance.

Reported childhood tuberculosis treatment outcomes, Gaborone and Francistown, Botswana, 1998-2002.

SETTING: Botswana. OBJECTIVES: To estimate frequencies of tuberculosis (TB) treatment outcomes, assess the validity of reported treatment outcomes, and identify risk factors for death during TB treatment among children aged <15 years during 1998-2002. DESIGN: We examined TB treatment outcome frequencies using the national Electronic TB Registry (ETR) data. Treatment and medical records were reviewed to calculate predictive values (PV) for outcomes recorded in the ETR. We interviewed parents of children treated for TB and assessed risk factors for death during treatment via case-control study. RESULTS: Of 5483 patients, 3646 (67%) were cured or completed treatment and 577 (10.5%) died during treatment. The PV for ETR was 76% for death and 97% for cured or completed treatment. We interviewed parents of 91 children who died during treatment and 220 children who completed treatment. Human immunodeficiency virus (HIV) status was unknown for 76% of the children and 54% of the parents. Parent-reported adverse effects to anti-tuberculosis medication (adjusted odds ratio [aOR] 4.9, 95% confidence limit [CL] 2.2-9.2), and lower patient age (aOR 2.2, 95%CL 1.2-4.2) were associated with death during treatment. CONCLUSIONS: TB control programs in Botswana should assess for potential adverse effects of anti-tuberculosis medication and expand HIV testing among children with TB and their parents.

Using program evaluation to improve the performance of a TB-HIV project in Banteay Meanchey, Cambodia.

SETTING: Cambodia has the highest human immunodeficiency virus (HIV) prevalence (1.9%) and tuberculosis (TB) incidence (508/100000) in Asia. Banteay Meanchey, a province with high HIV prevalence of 1.9%, established a pilot project in 2003 to enhance TB-HIV activities. We evaluated this project to improve performance. METHODS: In March 2005, we analyzed 17 months of data on all persons diagnosed with HIV or TB at 11 participating clinics. We determined barriers to HIV testing and TB screening, modified the program to reduce these barriers and assessed whether our interventions improved testing and screening rates. RESULTS: Among 952 patients newly diagnosed with TB disease, 138 (14%) had known HIV infection at the time of TB diagnosis. Of the 814 TB patients with unknown HIV status, 432 (53%) were HIV tested. Of 1228 persons newly diagnosed with HIV infection, 450 (37%) were screened for TB disease. We found and addressed barriers to HIV testing and TB screening. In the 9 months after the interventions, 240/322 (71%) TB patients were HIV tested, an increase of 34% (P < 0.01); 426/751 (57%) HIV-infected patients were screened for TB, an increase of 54% (P < 0.01). CONCLUSION: Evaluations of TB-HIV collaborative activities can lead to increased TB screening and HIV testing rates.

Baseline evaluation of routine HIV testing among tuberculosis patients in Botswana.

In January 2004, the government of Botswana introduced a policy of routine, non-compulsory human immunodeficiency virus (HIV) testing to increase testing and access to antiretroviral treatment (ART) for individuals presenting for medical treatment. Before a systematic implementation of the policy, we conducted a cross-sectional survey of tuberculosis (TB) record data from 46 clinics in 10 districts to assess baseline HIV testing rates among TB patients. Recorded HIV results from the facility TB register and TB treatment card were reviewed. Of the 1242 TB patients entered in the register, 47% had a recorded HIV result and 84% of these were co-infected with HIV. TB treatment cards were available for 862 (69%) registered patients. Among the 411 (47%) with test results recorded on the treatment card, 341 (83%) were HIV-infected; of these, 12% were reported to be receiving ART.

Treatment outcome and follow-up of multidrug-resistant tuberculosis patients, West Coast/Winelands, South Africa, 1992-2002.

SETTING: Brooklyn Chest Hospital, Western Cape, South Africa. OBJECTIVE: To evaluate the treatment outcome and 2- and 5-year follow-up of patients treated for multidrug-resistant tuberculosis (MDR-TB) with individualized regimens. DESIGN: Retrospective cohort study of all MDR-TB patients starting treatment during 1992-2002. Patients were evaluated every 6 months for 2 years after treatment and at 5 years when possible. RESULTS: Over 11 years, 491 (66%) of 747 MDR-TB patients received treatment with two or more second-line drugs; 239 (49%) were cured or completed treatment, 68 (14%) died, 144 (29%) defaulted from treatment, 27 (5%) failed, 10 (2%) transferred out and 3 (<1%) remained on treatment. Only 176 (36%) were tested for human immunodeficiency virus and 15 were positive. The proportion with a successful MDR-TB treatment outcome declined over time, while the proportion who defaulted remained stable. Among 410 patients who had not transferred out or died, 281 (69%) had 2-year data available: 185 (66%) were cured or completed treatment, 32 (11%) were retreated for TB and 64 (23%) died. CONCLUSIONS: Under program conditions in the West Coast/Winelands District, default rates were high and treatment success rates low. Outreach strategies for MDR-TB treatment should only be implemented if adequate resources are committed to the program.

Treatment outcome cohort analysis in an integrated DOTS and DOTS-Plus TB program in Latvia.

International guidelines for treatment outcome analysis of tuberculosis cases have been published and are widely used. They do not, however, fully address the incorporation of multidrug-resistant tuberculosis (MDR-TB) cases. Here we present an approach to cohort analysis of treatment outcomes for all registered TB cases, including MDR-TB cases. We analyzed all new pulmonary smear- and/or culture-positive cases registered in Latvia during 2002. Analysis of treatment outcomes at 24 months after initial case registration showed overall treatment success at 84%. This approach to outcome analysis is possible only for settings where MDR-TB treatment is established.

The epidemiology of HIV-associated tuberculosis in rural Cambodia.

SETTING: Banteay Meanchey Province, Cambodia. OBJECTIVE: The World Health Organization recommends human immunodeficiency virus (HIV) testing for all tuberculosis (TB) patients and TB screening for all HIV-infected persons in countries with a TB-HIV syndemic. We sought to determine whether evidence supports implementing these recommendations in South-East Asia. DESIGN: We conducted a cross-sectional survey and retrospective cohort study of patients newly diagnosed with HIV or TB from October 2003 to February 2005 to identify risk factors for HIV infection and TB, and for death during TB treatment. RESULTS: HIV infection was diagnosed in 216/574 (38%) TB patients. TB disease was found in 124/450 (24%) HIV-infected persons. No sub-groups of patients had a low risk of HIV infection or TB. Of 180 TB patients with HIV infection and a recorded treatment outcome, 49 (27%) died compared to 17/357 (5%) without HIV infection (relative risk [RR] 5.2, 95% confidence interval [CI] 3.1-8.7). HIV-infected TB patients with smear-negative pulmonary disease died less frequently than those with smear-positive pulmonary disease (RR 0.39, 95%CI 0.16-0.93). CONCLUSIONS: No sub-groups of patients had low risk for HIV infection or TB, and mortality among HIV-infected TB patients was high. These data justify using the WHO global TB-HIV recommendations in South-East Asia. Urgent interventions are needed to reduce the high mortality rate in HIV-infected TB patients.

Antituberculosis drug resistance and anonymous HIV surveillance in tuberculosis patients in Botswana, 2002.

Two surveys undertaken in Botswana in the 1990s have recorded low rates of antituberculosis drug resistance, despite a three-fold rise in tuberculosis since 1989. We undertook a third survey to determine both trends since 1995 and HIV prevalence in tuberculosis patients in Botswana. Sputum specimens were obtained from patients nationwide in 2002 who also underwent anonymous, rapid HIV testing by use of Oraquick. Of 2200 sputum smear-positive patients and 219 previously treated patients with suspected recurrent tuberculosis, 1457 (60%) were infected with HIV. Resistance to at least one drug in new patients rose from 16 (3.7%) isolates in 1995 to 123 (10.4%; p<0.0001) in 2002. Interventions for tuberculosis control are urgently needed in Botswana to prevent further emergence of drug resistance.

Risk factors associated with default from multidrug-resistant tuberculosis treatment, South Africa, 1999-2001.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) treatment centers in five provinces, South Africa. OBJECTIVES: To estimate the mortality and evaluate risk factors associated with default from MDR-TB treatment. DESIGN: Using registries and a standardized questionnaire, we conducted a case-control study among patients diagnosed and treated for MDR-TB. Cases were defined as patients who began MDR-TB treatment between 1 October 1999 and 30 September 2001 and defaulted from treatment for more than 2 months; controls were defined as patients who began MDR-TB treatment during the same time and were cured, completed or failed. RESULTS: After initial identification and reclassification, 269 cases and 401 controls were confirmed eligible for interview. Further investigation revealed that 74 (27%) cases and 44 (10%) controls had died. Among 96 cases located who consented and were interviewed, 70% had defaulted after receiving at least 6 months of treatment. In a multivariate model, the strongest individual risk factors for default included reporting smoking marijuana or mandrax during treatment, and having an unsatisfactory opinion about the attitude of health care workers. CONCLUSION: Mortality among MDR-TB defaulters was high. Interventions to reduce default from MDR-TB treatment should center on substance abuse treatment, patient education and support and improving provider-patient relationships.

Delamanid in the treatment of multidrug-resistant tuberculosis.

Otsuka has been engaged in anti-tuberculosis drug development efforts for over 30 years, and is the leading private sector funder of tuberculosis (TB) research and development. Delamanid (DLM), discovered by Otsuka's scientists, has been shown to provide benefit with respect to short-term surrogate markers and long-term treatment outcomes, and it has received regulatory approval for treatment of adult pulmonary multidrug-resistant TB (MDR-TB) as one of only two new anti-tuberculosis drugs in the last 40 years. Lack of drug-drug interactions with major antiretrovirals and efficacy against MDR-TB allow DLM's applicability in a wide range of MDR-TB patients. Current and future efforts are focused on replacing less safe and less efficacious second-line drugs with DLM, its contribution to all-oral and/or shortened treatment regimens, and, ultimately, inclusion in a pan-TB regimen. This manuscript provides a brief review of DLM.

TST reversion in a BCG-revaccinated population of nursing and medical students, São Paulo, Brazil, 1997-2000.

SETTING: A major university in São Paulo, Brazil, where vaccination against tuberculosis (TB) with bacille Calmette-Guerin (BCG) was routinely offered to first-year medical and nursing students. OBJECTIVES: To estimate the probability of negative tuberculin skin test (TST) results over a 4-year period following BCG revaccination, and to evaluate the effect of factors associated with reversion. DESIGN: Students were enrolled in 1997, initially given a two-step TST, and were retested annually or biannually for the duration of the study. Data on TB exposures and potential risk factors for TST negativity and reversion were collected through annual surveys. A linear mixture survival model was used to estimate the probability of negative TST results over time. RESULTS: Of 159 students, an estimated 20% had a negative TST result despite revaccination, and a further 31% reverted to negative over 4 years of follow-up. No cofactors significantly affected the probability of reversion. CONCLUSION: Overall, in the absence of reported exposure to Mycobacterium tuberculosis, 51% of students revaccinated upon entering nursing or medical school would have a negative TST result by the time they begin their internships. In this recently vaccinated population, reversion was common, suggesting that annual TST screening may remain a useful tool.

Capacity building for international tuberculosis control through operations research training.

SETTING: In resource-poor countries, few tuberculosis (TB) program staff at the national, provincial, and even district levels have the basic analytical and epidemiological skills necessary for collecting and analyzing quality data pertaining to national TB control program (NTP) improvements. This includes setting program priorities, operations planning, and implementing and evaluating program activities. OBJECTIVES: To present a model course for building capacity in basic epidemiology and operations research (OR). DESIGN: A combination of didactic lectures and applied field exercises were used to achieve the main objectives of the 6-day OR course. These were to increase the understanding of quantitative and qualitative research concepts, study design, and analytic methods, and to increase awareness of how these methods apply to the epidemiology and control of TB; and to demonstrate the potential uses of OR in answering practical questions on NTP effectiveness. As a final outcome, course participants develop OR proposals that are funded and later implemented. RESULTS: Since 1997, this OR course has been conducted nine times in five countries; 149 key NTP and laboratory staff have been trained in OR methods, and 44 OR protocols have been completed or are underway. CONCLUSION: This low-cost model course can be adapted to a wide range of public health issues.

New international efforts in childhood tuberculosis: proceedings from the 2002 Workshop on Childhood Tuberculosis, Montreal, Canada, 6-7 October 2002.

On 6-7 October 2002, the International Union Against Tuberculosis and Lung Disease (IUATLD), the International Pediatrics Association (IPA), the United States Centers for Disease Control and Prevention (CDC), the United States National Institutes for Health (NIH), and the World Health Organization (WHO) co-sponsored and organized a Workshop on 'Tuberculosis in Children' to assess research needs in childhood tuberculosis (TB) in conjunction with the 33rd IUATLD World Conference on Lung Health. Participants included approximately 40 researchers from the sponsoring organizations as well as from academic institutions, and National Tuberculosis (TB) Programs from a number of countries in sub-Saharan Africa, Asia, Latin America, and Eastern Europe. The goals of the workshop were to highlight current gaps in knowledge about childhood TB, to assess research opportunities, and to begin to establish working partnerships and identify funding sources. The workshop focused on six key topics: the global epidemiology of TB among children, clinical practice including diagnosis and case management of childhood TB, basic research, programmatic aspects of the control of TB among children, ethics, and effects of human immunodeficiency virus (HIV) on TB in children. Review papers on these topics were presented as the foundation for the workshop. Participants were then divided into groups to deliberate on critical areas of research and programmatic needs, recommendations for addressing the needs, and strategic planning to increase international focus on childhood TB. The following summary, including data reported and referenced within the review papers presented at the workshop, represents the proceedings of the workshop.

Global epidemiology of childhood tuberculosis.

Tuberculosis (TB) in children has been less of a public health priority in recent years, despite the fact that TB is an important cause of childhood morbidity and mortality worldwide. Data on trends in childhood TB are scarce in the published literature. The diagnosis of TB in children is difficult, and rarely rests on bacteriologic confirmation. Surveillance data for children in many countries are lacking and there are few epidemiologic studies. However, in regions of the world such as sub-Saharan Africa where adult TB is increasing, this trend is likely occurring among children as well. This review documents an increase in childhood TB in many parts of the world. Risk factors vary by region. Improvements in global surveillance of childhood TB, investigation of the role of national TB programs (NTPs) in improving the control of childhood TB, and better identification of risk factors for childhood disease will be crucial to future control efforts for childhood TB. This might include assessment of optimal methods of contact investigations and an analysis of NTP data to assess risk factors for adverse outcomes (e.g., death, default, treatment failure) among children. Ultimately, these data will ensure the success of interventions to reduce the burden of childhood TB using strategies that specifically target this population. As children represent the future burden of TB disease, these efforts could significantly reduce the overall global burden of TB in years to come.

Occupational risk from ultraviolet germicidal irradiation (UVGI) lamps.

The recommended role of ultraviolet germicidal irradiation (UVGI) is to reduce the risk of tuberculosis (TB) transmission in health care facilities. However, excess exposure may result in dermatosis and photokeratitis. In one hospital setting in Botswana, two nurses and one housekeeper complained of eye discomfort, 'like sand in the eyes', after working in an administrative office. The following day, one employee noted facial skin peeling. All symptoms resolved over 2-4 days without sequelae. Six weeks later, the syndrome recurred for all three employees. A workplace investigation revealed that the office had been converted from a hospital sputum induction room, and that an unshielded 36-W UVGI lamp was still installed and operational. The on/off switch for the UVGI lamp was immediately adjacent to the fluorescent bulb on/off switch, and did not have a locking mechanism. The US National Institute for Occupational Safety and Health recommends that exposure to UVGI (254 nm) be less than 6000 microJ/cm2 (6000 microW approximately = sec/cm2) over a daily 8-hour period on unprotected skin or eyes. In the office, UVGI measurements at eye level and looking directly at the UVGI lamp ranged from a low of 20.0 microW approximately = sec/cm2 when seated to a high of 49.9 microW approximately = sec/cm2 when standing. These irradiance levels result in allowable exposure times of 300 and 120 seconds, respectively, and are the most likely cause of the clinical syndrome described.

The importance of quality control of sputum smear microscopy: the effect of reading errors on treatment decisions and outcomes.

SETTING: Ho Chi Minh City, Vietnam. OBJECTIVE: To evaluate the impact of slide reading errors at peripheral level on case-finding and treatment decisions. DESIGN: Over a 6-month period in 1997, information on date, type of slide, results of other slides from the patient, and treatment status was collected for all slides from district TB centers detected as having reading errors during smear microscopy quality control re-readings. RESULTS: Reading errors were detected in 117 slides: 115 (98.3%) were incorrectly read as negative, and 75 (65.2%) of these errors occurred in case-finding slides. In the 75 falsely negative case-finding slides, re-reading resulted in initiation of treatment in 38 patients (50.7%). The remaining 37 (49.3%) had only one positive slide and were told to return for follow-up after 6 months; the two (5.4%) who did return were both diagnosed with active TB. Detection of errors in the 40 false-negative follow-up slides resulted in treatment changes in four patients (10%). CONCLUSIONS: Quality control plays a critical role in helping to ensure the timely diagnosis and treatment of new TB cases and appropriate management of patients currently on treatment. The usefulness of quality control could be enhanced by focusing greater efforts on case-finding slides initially read as negative.

Quality control of smear microscopy for acid-fast bacilli: the case for blinded re-reading.

SETTING: Quality control of sputum smear microscopy, which is essential for ensuring correct tuberculosis (TB) diagnosis, is often performed through the unblinded rereading of all positive slides and a sample of negative slides. OBJECTIVE: To assess misclassification error introduced by knowledge of prior results. METHODS: The Southern Vietnam Regional TB Laboratory prepared three gold-standard sets of 750 slides: an unblinded set, an unblinded set in which 13% of negative slides were replaced by weakly positive slides purposefully mislabelled as negative, and a blinded set. Six provincial technicians who normally perform district quality control each reread 125 slides from each set. RESULTS: In the three sets only one negative slide was misread as positive. In the unblinded set (referent), 2.9% (9/311) positive slides were misread as negative, compared with 18.7% (57/305) in the blinded set (prevalence ratio [PR] = 6.5; 95% confidence interval [CI] 3.3-12.8; P < 0.001), and 11.3% (33/293) in the unblinded set with mislabelled slides (PR = 3.9; 95%CI 1.9-8.0; P < 0.001). CONCLUSIONS: False-negative error was more common than false-positive error. Knowledge of prior reading influences re-reading. Blinded re-reading of systematically selected slides would appear preferable, although this method requires high levels of proficiency among quality control technicians.

The validity of HIV testing using sputum from suspected tuberculosis patients, Botswana, 2001.

SETTING: The World Health Organization recommends that sentinel HIV surveillance be conducted on tuberculosis patients. However, serum HIV testing is complicated in the TB clinic context, and may not be acceptable to patients. DESIGN: To determine the utility of the OraQuick HIV-1/2 Assay for the detection of HIV antibodies in sputum, we consecutively enrolled adult in-patients in Botswana who had sputum sent for acid-fast bacilli testing and serum sent for HIV ELISA testing. OraQuick HIV-1/2 Assay was applied to gingival secretions according to manufacturer's guidelines, and was also dipped into sputum specimens. A subset of 60 sputum specimens was also serially tested up to 72 hours after collection. RESULTS: Of 377 patients, 84% were HIV-positive by serum ELISA. Compared with serum ELISA, the OraQuick HIV-1/2 Assay detected HIV in gingival secretions with 98.4% sensitivity and 98.3% specificity (95%CI 97-99 and 92-100, respectively), and 97.1% sensitivity and 98.3% specificity on initial sputum specimens (95%CI 95-99 and 92-100, respectively). OraQuick HIV-1/2 Assay performance on sputum declined slightly when tested up to 72 hours after collection. CONCLUSIONS: When applied to sputum specimens, the OraQuick HIV-1/2 Assay demonstrates sensitivity and specificity comparable to its intended application on gingival secretions. This novel testing method will be valuable in anonymous sentinel HIV surveillance surveys among tuberculosis patients.

Pain and electrophysiological parameters are improved by combined 830-1064 high-intensity LASER in symptomatic carpal tunnel syndrome versus Transcutaneous Electrical Nerve Stimulation. A randomized controlled study.

AIM: The aim of the study was to compare LASER versus transcutaneous electrical nerve stimulation (TENS) in reducing pain and paraesthesia; and in improving motor and sensory median nerve conduction parameters in mild to moderate carpal tunnel syndrome (CTS). DESIGN: Randomised blinded pilot study. Patients and staff administered treatments and outcome measures were blinded. SETTING: Outpatient; Research and Care Rehabilitation Institute. PARTICIPANTS: Twenty CTS symptomatic patients. INTERVENTIONS: Fifteen sessions of: 1) 100 Hz TENS (30 minutes; rectangular waves; 80 ms width, intensity below muscle contraction); 2) combined 830-1064 nm LASER (radiating dose: 250 J cm-2 delivered to the skin overlying the course of the median nerve at the wrist for 100 s at 25 W (18 W [1064 nm] + 7 W [830 nm]) via a fiber-optic probe with a spot size of ~1 cm2). Outcome measures. Visual analogue scale (VAS) for pain and paresthesia; median nerve distal motor latency and sensory nerve conduction velocity. RESULTS: LASER improved both positive and negative sensory symptoms. TENS induced clinical improvement but this was not statistically significant and was limited to pain reduction. LASER but not TENS favourably modified the neurophysiological parameters. CONCLUSION: High-intensity combined LASER wavelengths of 830 nm and 1064 nm, which produce a better transparency with less scattering and a high energy transfer, are better than TENS in improving both pain and paraesthesia as well as neurophysiological parameters in CTS.

LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap.

The liver kinase B1 (LKB1) tumor suppressor inhibits cell growth through its regulation of cellular metabolism and apical-basal polarity. The best understood mechanism whereby LKB1 limits cell growth is through activation of the AMP-activated-protein-kinase/mammalian-target-of-rapamycin (AMPK/mTOR) pathway to control metabolism. As LKB1 is also required for polarized epithelial cells to resist hyperplasia, it is anticipated to function through additional mechanisms. Recently, Yes-associated protein (Yap) has emerged as a transcriptional co-activator that modulates tissue homeostasis in response to cell-cell contact. Thus this study examined a possible connection between Yap and LKB1. Restoration of LKB1 expression in HeLa cells, which lack this tumor suppressor, or short-hairpin RNA knockdown of LKB1 in NTERT immortalized keratinocytes, demonstrated that LKB1 promotes Yap phosphorylation, nuclear exclusion and proteasomal degradation. The ability of phosphorylation-defective Yap mutants to rescue LKB1 phenotypes, such as reduced cell proliferation and cell size, suggest that Yap inhibition contributes to LKB1 tumor suppressor function(s). However, failure of Lats1/2 knockdown to suppress LKB1-mediated Yap regulation suggested that LKB1 signals to Yap via a non-canonical pathway. Additionally, LKB1 inhibited Yap independently of either AMPK or mTOR activation. These findings reveal a novel mechanism whereby LKB1 may restrict cancer cell growth via the inhibition of Yap.