Informed patient consent for defaulter tracing: should we obtain it?

Active default tracing is an integral part of tuberculosis (TB) programmatic control. It can be differentiated into the tracing of defaulters (patients not seen at the clinic for > or =2 months) and 'late patients' (late for their scheduled appointments). Tracing is carried out to obtain reliable information about who has truly died, transferred out or stopped treatment, and, if possible, to persuade those who have stopped treatment to resume. This is important because, unlike routine care for non-communicable diseases, TB has the potential for transmission to other members of the community, and therefore presents the issue of the rights of the individual over the rights of the community. For this reason, default or 'late patient' tracing (defined together as default tracing in this article) has been incorporated into standard practice in most TB programmes and, in many industrialised countries, it is also a part of public health legislation. In resource-poor countries with limited access to phones or e-mails, default tracing involves active home visits. In this Unresolved Issues article, we discuss the need for patient consent within both the programmatic and the research context; we describe how this subject arose during operational research training at the Research Institute of Tuberculosis in Japan; we provide comments from individuals who are experienced and skilled at international and national TB control; and finally we offer some conclusions about the way forward. This is not an easy subject, and we welcome open debate on the issue.

Determinants of tuberculosis diagnosis and the role of counselling.

OBJECTIVE: To study patient determinants that may affect completion of the diagnostic process in tuberculosis control, highlighting the role of counselling. DESIGN: Cross-sectional study. SUBJECTS: TB patients. SETTING: Rhodes Chest Clinic, Nairobi, City Council. RESULTS: Ninety five percent of the suspects delivered three sputum samples but only 27% consented to a HIV test; several determinants for none consenting were mentioned. On average US$2.27 was spent for one clinic visit and U.S. $8.62 for following the entire diagnostic process. Cost factors included transport, loss of income and food. CONCLUSION: Individual pre-test counselling seems important for obtaining three sputum specimens. It takes time and for settings with a large number of suspects, alternative methods may be required. To obtain consensus for a HIV test in a TB clinic is complicated. Costs spent on transport and loss in income are important determinants and may contribute to poor patient adherence to the diagnostic process.

The role and performance of chest X-ray for the diagnosis of tuberculosis: a cost-effectiveness analysis in Nairobi, Kenya.

BACKGROUND: The objective of this study was to establish 1) the performance of chest X-ray (CXR) in all suspects of tuberculosis (TB), as well as smear-negative TB suspects and 2) to compare the cost-effectiveness of the routine diagnostic pathway using Ziehl-Neelsen (ZN) sputum microscopy followed by CXR if case of negative sputum result (ZN followed by CXR) with an alternative pathway using CXR as a screening tool (CXR followed by ZN). METHODS: From TB suspects attending a chest clinic in Nairobi, Kenya, three sputum specimens were examined for ZN and culture (Lowenstein Jensen). Culture was used as gold standard. From each suspect a CXR was made using a four point scoring system: i: no pathology, ii: pathology not consistent for TB, iii: pathology consistent for TB and iv: pathology highly consistent for TB. The combined score i + ii was labeled as "no TB" and the combined score iii + iv was labeled as "TB". Films were re-read by a reference radiologist. HIV test was performed on those who consented. Laboratory and CXR costs were used to compare for cost-effectiveness. RESULTS: Of the 1,389 suspects enrolled, for 998 (72%) data on smear, culture and CXR was complete. 714 films were re-read, showing a 89% agreement (kappa value = 0.75 s.e.0.037) for the combined scores "TB" or "no-TB". The sensitivity/specificity of the CXR score "TB" among smear-negative suspects was 80%/67%. Using chest CXR as a screening tool in all suspects, sensitivity/specificity of the score "any pathology" was 92%, respectively 63%. The cost per correctly diagnosed case was for the routine process 8.72 dollars, compared to 9.27 dollars using CXR as screening tool. When costs of treatment were included, CXR followed by ZN became more cost-effective. CONCLUSION: The diagnostic pathway ZN followed by CXR was more cost-effective as compared to CXR followed by ZN. When cost of treatment was also considered CXR followed by ZN became more cost-effective. The low specificity of chest X-ray remains a subject of concern. Depending whether CXR was performed on all suspects or on smear-negative suspects only, 22%-45% of patients labeled as "TB" had a negative culture. The introduction of a well-defined scoring system, clinical conferences and a system of CXR quality control can contribute to improved diagnostic performance.

Cost-effectiveness of polymerase chain reaction versus Ziehl-Neelsen smear microscopy for diagnosis of tuberculosis in Kenya.

BACKGROUND: Laboratory services, particularly in large sub-Saharan cities, are overstretched, and it is becoming difficult both for patients and health staff to adhere to the diagnostic procedures for tuberculosis. Alternative techniques would be welcome. The polymerase chain reaction (PCR) has the potential to be cost-effective. We compared the cost-effectiveness of two diagnostic strategies, Ziehl-Neelsen (ZN) on three specimens followed by chest X-ray (CXR), and AMPLICOR MTB PCR on the first specimen only. METHODS: Three sputum samples were collected from tuberculosis (TB) suspects attending the Rhodes Chest Clinic, Nairobi. All samples were subjected to ZN, PCR and Löwenstein-Jensen culture used as gold standard. CXR was used to diagnose smear-negative TB. Cost analysis included health service and patient costs. RESULTS: Costs per correctly diagnosed case were US dollar 41 and dollar 67 for ZN and PCR, respectively. When treatment costs were included, including treatment of culture-negative cases, PCR was more cost-effective: dollar 382 vs. dollar 412. CONCLUSION: PCR may be an alternative in settings with many patients. PCR is patient friendly, CXR is not necessary and, unlike ZN, its performance is hardly affected by the human immunodeficiency virus. PCR can handle large numbers of specimens, with results becoming available on the same day.

Sex-specific performance of routine TB diagnostic tests.

SETTING: City Council Chest Clinic, Nairobi, Kenya. OBJECTIVE: To determine to what extent the performance of smear microscopy is responsible for sex differences in notification rates. METHODOLOGY: Three sputum samples from TB suspects were subjected to smear microscopy with Ziehl-Neelsen (ZN) and auramine (FM) staining. Lowenstein-Jensen culture was used as the gold standard. RESULTS: Of 998 suspects, 600 (60%) were men and 398 (40%) women. The odds of detecting culture-positive patients with ZN was lower for women (OR 0.67). By examining the first spot specimen, ZN detected 35% of culture-positive males and 26% of culture-positive females. These proportions increased to respectively 63% and 53% when examining three specimens, and to 79% and 74% when using FM. The sex difference reduced and became non-significant (P = 0.19) when adjusted for HIV; however, the numbers involved for HIV stratification were low. CONCLUSION: The performance of a diagnostic tool contributes to sex differences in notification rates and influences male/female ratios. Women were less likely to be diagnosed (P = 0.08), and when ZN was used they were less likely to be labelled as smear-positive TB (P < 0.01). The application of more sensitive diagnostic tools such as FM is to the advantage of women.

A comprehensive comparison of Ziehl-Neelsen and fluorescence microscopy for the diagnosis of tuberculosis in a resource-poor urban setting.

SETTING: Nairobi City Council Chest Clinic, Kenya. OBJECTIVES: To establish the efficiency, costs and cost-effectiveness of six diagnostic strategies using Ziehl-Neelsen (ZN) and fluorescence microscopy (FM). DESIGN: A cross-sectional study of 1398 TB suspects attending a specialised chest clinic in Nairobi subjected to three sputum examinations by ZN and FM. Lowenstein-Jensen culture was used as the gold standard. Cost analysis included health service and patient costs. RESULTS: Of 1398 suspects enrolled, 993 (71%) had a complete diagnostic work-up involving three sputum specimens for ZN and FM, culture and chest X-ray (CXR). Irrespective of whether ZN or FM was used on one, two or three smears, the overall diagnostic process detected 92% culture-positive cases. Different strategies affected the ratio of smear-positive to smear-negative TB; however, FM was more sensitive than ZN (P < 0.001). FM performance was not affected by the patient's HIV status. The cost per correctly diagnosed smear-positive case, including savings, was 40.30 US dollars for FM on two specimens compared to 57.70 US dollars for ZN on three specimens. CONCLUSION: The FM method used on one or two specimens is more cost-effective and shortens the diagnostic process. Consequently, more patients can be put on a regimen for smear-positive TB, contributing to improved treatment and reducing transmission.

A comprehensive study of the efficiency of the routine pulmonary tuberculosis diagnostic process in Nairobi.

Tuberculosis (TB) suspects from Rhodes Chest Clinic, Nairobi, Kenya, were subjected to three sputum smear microscopy (Ziehl-Neelsen) examinations and a chest X-ray (CXR). Results were compared with Löwenstein-Jensen culture as the gold standard to establish the efficiency of the routine diagnostic process. All laboratory tests and the CXR were available for 993 (71%) of the 1,398 enrolled suspects. Of these, 554 (56%) were culture-positive. The routine diagnostic process was very sensitive, able to detect 92% of culture-positive cases but missing 8%. The specificity was low (66%), and 23% of the patients started on treatment were culture-negative, mainly due to the low specificity of the CXR. It may be possible to increase the efficiency of the diagnostic process by specifying better criteria for CXR examination, improving the quality of CXR reading and counselling patients to return when complaints persist.

Why do patients with a cough delay seeking care at Lusaka urban health centres? A health systems research approach.

SETTING: Primary health centres in urban Lusaka, Zambia. OBJECTIVES: To describe the distribution and risk factors for delay among patients presenting with a cough to the urban health centres. DESIGN: A health systems research methodology was used. A participatory workshop analysed the problem and designed a cross-sectional survey of patients attending two urban health centres. Initial data analyses were performed in a second workshop, with results discussed with a broad range of policy-makers, health care staff and community members interested in tuberculosis. RESULTS: A total of 427 patients were interviewed; 35% had delayed for more than one month. Delay was associated with older age, severe underlying illness, poor perception of the health services, distance from the clinic and prior attendance at a private clinic. There was no relationship between delay and knowledge about tuberculosis, nor with education, socio-economic level or gender. Tuberculosis and HIV were felt to be closely linked and highly stigmatised, but stigmatising attitudes were not associated with longer delays. CONCLUSIONS: The health systems research methodology was an effective way to engage the staff of the district health services in action-oriented research. Investing in improvements in the health system and ensuring accessibility for older and more disabled patients is likely to reduce delays in diagnosis and help to improve tuberculosis control in Lusaka.

Short-course instead of long-course chemotherapy for smear-negative patients in sub-Saharan Africa.

The use of short-course chemotherapy (SCC) in directly-observed treatment, short-course (DOTS) programmes in sub-Saharan Africa was often restricted to patients with infectious and serious forms of tuberculosis, because of high costs of such regimens. With reduced drug prices and wide-scale substitution of thiacetazone by ethambutol in the continuation phase of treatment, various short-course regimens are now available at the same or even lower costs than long-course regimens. Several DOTS programmes are considering extending access to short-course chemotherapy to non-infectious patients, or have done so already. The authors provide an overview of the issues regarding the debate on the introduction of universal SCC in national tuberculosis control programmes in low-income countries in sub-Saharan Africa. They advise on a low-risk strategy to avoid the emergence of rifampicin resistance as a consequence of the wide availability of rifampicin associated with universal short-course, and strengthening of the health system to maintain high performance levels in diagnosis and treatment.

Trend in the annual risk of tuberculous infection in Egypt, 1950-1996.

OBJECTIVE: To determine the trend in the risk of tuberculous infection in non-BCG vaccinated children in Egypt in the period 1950-1996. METHODS: In 1949-1952, a tuberculin survey was carried out in Egypt by the World Health Organization (WHO) covering 103 districts. In 1995-1997 a tuberculin survey was carried in 73 620 primary school children in grade one in the same districts, using international guidelines. The trend in tuberculous infection was determined by comparing the prevalence of Mantoux reactions of > or =6 mm in the two surveys in subjects without apparent BCG scar aged 6-7 years. For an estimate of current risk of infection the 17 mm cut-off point (number with 17 mm plus twice the number with greater than 17 mm) was used. RESULTS: In 1995-1997, 76% of children had a BCG scar. Infection prevalence estimates in 14 766 non-BCG-vaccinated children with a mean age of 6.7 years were 11.9%, 4.1%, and 2.1% for the cut-off points 6 mm, 10 mm, and 17 mm, respectively. Decline in the risk of infection was estimated to be in the order of 50% over 45 years, or 1.5% per year. The geometric mean annual risk of infection in the 6.7 years before the survey was estimated at 0.32% (95% confidence interval 0.27-0.40%). For Egypt, the incidence of smear-positive tuberculosis was estimated at 16 per 100000 population, giving a case detection rate of 85% (range 56-100%). CONCLUSION: This survey has shown that the size of the tuberculosis problem in Egypt is considerably smaller now than it was 45 years ago.

Cost-effectiveness of the polymerase chain reaction versus smear examination for the diagnosis of tuberculosis in Kenya: a theoretical model.

SETTING: A major out-patient tuberculosis clinic in Nairobi, Kenya. OBJECTIVE: To ascertain the cost-effectiveness of the polymerase chain reaction (PCR) for the diagnosis of tuberculosis in an urban setting in a developing country. DESIGN: A cost-effectiveness analysis of PCR and direct smear microscopy examination based on theoretical modelling. The cost-effectiveness was expressed in costs per correctly diagnosed tuberculosis patient for each of the two diagnostic techniques. Data were obtained from the literature, from the staff and the register at the health facility and from structured interviews with patients. Assumptions were made when no data were available. RESULTS: The PCR is expected to be more specific and sensitive than the routine procedure for diagnosis, but it is also more costly. The routine procedure based on direct smear microscopy turned out to be 1.8 times as cost-effective as PCR. CONCLUSION: It is concluded that the PCR method can potentially be a cost-effective screening procedure for tuberculosis, provided that the largest contributing cost component, the costs of the PCR-kit, can be reduced substantially.

The proportion of tuberculosis cases in Tanzania attributable to human immunodeficiency virus.

BACKGROUND: Routine data obtained from the National Tuberculosis and Leprosy Programme (NTLP) of Tanzania have shown a constant increase in the notified number of tuberculosis (TB) cases since 1982. Possible causes include an improved reporting system, improvement in health services after the introduction of short course chemotherapy (SCC), and human immunodeficiency virus (HIV) infection. This paper examines to what extent the increased TB case detection rate can be attributed to HIV infection, by calculating the population attributable risk for various years. METHOD: The prevalence of HIV infection was obtained from data of the National AIDS Control Programme and the relative risk of HIV for developing TB from a case-control study and the literature. RESULTS: Between 1985 and 1989 the increase was the highest among women aged 15-24 years and men aged 25-34 years; age groups in which HIV prevalence is highest. In the case-control study HIV prevalence among blood donors was 9.4% and among smear-positive pulmonary TB patients 51.6%, giving an odds ratio (OR) of 8.1 (95% confidence interval (CI): 4.4-16.3). For all TB cases the OR was 11.8. In a population with an HIV prevalence of 10%, about 40% of the smear-positive TB patients are attributable to HIV. The excess of TB cases in the entire country between 1982 and 1989 can be attributable to HIV infection. This has implications for TB control and socioeconomic consequences in the country.

PIP: The increase seen in the incidence of tuberculosis (TB) in many developing countries in the early 1980s was at first through to be the result of better case detection, but it soon became clear that HIV infections were influencing this increase. To determine the extent that HIV infection has increased TB case detection rates in Tanzania, data were analyzed from the National TB and Leprosy Programme, the National AIDS Control Programme, and a case-control study conducted for three months in 1990. Cases were all 128 newly registered cases of TB in three districts. Controls were 1558 blood donors in these districts. HIV prevalence among the cases was 51.6%, with no differences in sex, residence, or type of TB. HIV prevalence was highest among 25-34 year olds. HIV prevalence in controls was 9.4%, with no variation by age or sex. The odds ratio for association between HIV infection and new smear-positive TB, stratified by age, was 8.1. The age-stratified offs ratio for HIV infection and any type of TB was 11.8. The population attributable risk for 1990 was in the order of 30%, which means that, without HIV, the increase in TB cases seen after 1985 would not have occurred. It is essential to improve TB programs to minimize the looming increase in the annual risk of infection. Also, HIV control programs will have a large effect on TB control programs, and collaboration between the two should be encouraged.

Radiosensitivity of parenchymal hepatocytes as a function of oxygen concentration.

To investigate the mechanism(s) of hepatocyte radioresistance (D0 2.7 Gy), the radiosensitivities of respiring (37 degrees C) and nonrespiring (0 degrees C) hepatocytes were determined as a function of oxygen concentration. Fischer 344 female rat hepatocytes were isolated by liver perfusion, equilibrated in Leibowitz-15 media with different oxygen tensions, and exposed to 60Co radiation at either 37 or 0 degrees C. Cell survival and DNA single-strand breaks were used as the biological end points of radiosensitivity. The K value for respiring hepatocytes (37 degrees C) was 14.3 +/- 0.5 mm Hg O2 (18.8 +/- 0.7 mumol O2/liter), demonstrating that the K value for freshly isolated parenchymal hepatocytes is significantly greater than those previously obtained for cultured cells. In contrast, the K value for nonrespiring hepatocytes (0 degree C) is 1.4 +/- 0.4 mm Hg O2 (3.7 +/- 1.0 mumol O2/liter) indicating that hepatocyte respiration results in a plasma membrane-to-nucleus oxygen gradient of approximately 12.9 +/- 0.6 mm Hg (15.1 +/- 1.2 microns O2/liter). The hypothesis that the hepatic nucleus typically resides in a hypoxic condition, although the liver is uniformly perfused with well-oxygenated blood, is supported by (1) the nonradom perinuclear distribution of the mitochondria, (2) the high cellular respiration rate, and (3) the large intracellular oxygen diffusion distance in hepatocytes (25 microns diameter).

Radiation sensitivity of adult human parenchymal hepatocytes.

The radiosensitivity of human hepatocytes was determined and compared to that of rat hepatocytes. This interspecies comparison was performed by using the alkaline elution technique to measure DNA single-strand breaks and their repair in irradiated primary cultures of hepatocytes. Human hepatocytes obtained from discarded surgical material and Fischer 344 female rat hepatocytes were enzymatically dispersed with collagenase, placed in culture, and irradiated with 0, 10, 20, and 40 Gy of 60Co gamma rays. The DNA was eluted either immediately after irradiation or at different times following incubation at 37 degrees C to allow for DNA single-strand break repair. The slopes of the dose-response relationship (strand scission factor versus dose) without DNA repair were 0.014 +/- 0.002 Gy-1 (n = 5) and 0.018 +/- 0.003 Gy-1 (n = 12) in human and rat hepatocytes, respectively; they were not significantly different. The half-time for fast and slow repair in human and rat hepatocytes was also not significantly different (i.e., 17.8 +/- 4.4 min and 253 +/- 67 min, and 13.9 +/- 6.1 min and 121 +/- 31 min, respectively), and 15 to 25% of the initial radiation-induced DNA damage was still present after 3 h of repair.