Whole-genome sequencing for TB source investigations: principles of ethical precision public health.

BACKGROUND: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis allows rapid, accurate inferences about the sources, location and timing of transmission. However, in an era of heightened concern for personal privacy and science distrust, such inferences could result in unintended harm and undermine the public´s trust.METHODS: We held interdisciplinary stakeholder discussions and performed ethical analyses of real-world illustrative cases to identify principles that optimise benefit and mitigate harm of M. tuberculosis WGS-driven TB source investigations.RESULTS: The speed and precision with which real-time WGS can be used to associate M. tuberculosis strains with sensitive information has raised important concerns. While detailed understanding of transmission events could mitigate harm to vulnerable patients and communities when otherwise unfairly blamed for TB outbreaks, the precision of WGS can also identify transmission events resulting in social blame, fear, discrimination, individual or location stigma, and the use of defaming language by the public, politicians and scientists. Public health programmes should balance the need to safeguard privacy with public health goals, transparency and individual rights, including the right to know who infects whom or where.CONCLUSIONS: Ethical challenges raised by real-time WGS-driven TB source investigation requires public health authorities to move beyond their current legal mandate and embrace transparency, privacy and community engagement.

False-positive rifampicin resistance on Xpert® MTB/RIF caused by a silent mutation in the rpoB gene.

The Xpert® MTB/RIF assay detects the presence of Mycobacterium tuberculosis and its resistance to rifampicin (RMP) directly in sputum samples. Discrepant results were observed in a case of smear-positive pulmonary tuberculosis that was Xpert-resistant but phenotypically susceptible to RMP. Complementary investigations (repeat Xpert, Genotype®MTBDRplus assay and sequencing of the rpoB gene) revealed the presence of a silent mutation in the rpoB gene, leading to the conclusion of a false-positive Xpert result. As misinterpretation of Xpert results may lead to inappropriate treatment, the presence of rpoB mutations should be confirmed by sequencing the rpoB gene.

Trends in prevalence and case finding in the ALERT leprosy control programme, 1979-1999.

From 1979 to 1999, the ALERT leprosy control programme has covered a well-defined area in central Ethiopia using standardized case finding strategies. During this period, the leprosy prevalence has decreased more than 30-fold, there has been a 3-fold decrease in case detection and a 6-fold decrease in the case detection rate. The proportion of MB patients among new cases increased by around 80% and the proportion of children among new cases decreased by around 60%. Several factors may have contributed to these trends. The impact of the introduction of MDT and the shortening of the duration of the MB regimen are shown, but other factors are also discussed at length: an increase in the population of the area, cleaning up of the registers, changing case definitions, changes in staff motivation and fluctuations, even small ones, in case finding intensity and coverage. Do the observed trends reflect a reduction in the transmission of the leprosy infection? Because of the many confounding factors, it would be difficult to answer that question positively at present. Additional rigorous data collection and analysis is required.

Which physical signs help most in the diagnosis of leprosy? A proposal based on experience in the AMFES project, ALERT, Ethiopia.

As integration of leprosy control programmes proceeds, general health staff will have responsibility for the diagnosis of most new cases of leprosy. The training required by these workers has not yet been set out in detail. In this paper the criteria for making the diagnosis of leprosy in the AMFES cohort of 594 new cases are examined. Since this study does not include details of suspects in whom leprosy was excluded on clinical grounds, true sensitivity and specificity values cannot be calculated, but the positive predictive value of the diagnostic criteria can be measured. Sensory loss in a typical skin patch is the most important sign of early leprosy, but was not present in 132 (49%) of the 268 cases with a positive skin smear. Thickening of the ulnar nerve is a valuable sign of leprosy in Ethiopia. It can be taught to health workers, who can practise by examining their own ulnar nerves. It is more likely to be present than nerve function impairment and is particularly important when skin smears are difficult to do or are unreliable. We recommend that five basic signs are used, the presence of any two being diagnostic of leprosy: Skin lesion(s) consistent with leprosy. Loss of sensation in such a lesion. Thickening of either ulnar nerve. Loss of sensation in the palm of the hand or the sole of the foot. The presence of acid-fast bacilli in skin smears. Exact policies for the diagnosis of leprosy should be worked out and validated for each national programme.

Classification of leprosy cases under field conditions in Bangladesh. I. Usefulness of skin-smear examinations.

In 2 non-governmental organization projects in Bangladesh 244 new leprosy patients were classified in the field according to clinical criteria. Skin smears were taken at 4 standardized sites and at the most active peripheral lesion, where a biopsy was also taken. Comparison of the clinical field classification with the results of the skin smears and biopsies gives a sensitivity of 92.1% for the clinical criteria, but a specificity of only 41.3%. The skin-smear results, on the other hand, have a sensitivity of 88.4% and a specificity of 98.1%. Thus, skin smears may contribute considerably to the operational classification of leprosy patients under field conditions. Quality control of the peripheral laboratory is essential. Appropriate site selection for the smear taking will also contribute to increased performance. Analysis of the skin-smear results suggests that the policy of taking smears at standardized sites should be abandoned in favour of the earlobes and active peripheral lesions.

Classification of leprosy cases under field conditions in Bangladesh. II. Reliability of clinical criteria.

In 2 non-governmental organization projects 244 new leprosy patients in Bangladesh were classified in the field according to clinical criteria i.e. number of skin lesions and number of enlarged nerves. Comparison of these classification results with the results of skin smears and biopsies yielded a sensitivity (for detection of a MB case) of 92.1%, but the 'unconfirmed MB rate' amounted to 52.6%. In order to improve the reliability of the operational classification, several additional clinical criteria were investigated. It was found that neither the presence of anaesthesia in the skin lesions nor the presence of grade 2 disabilities or peripheral anaesthesia or voluntary muscle testing (VMT) impairment contributed to an improved classification. Counting the number of body areas showing signs of leprosy, which had proven very useful in other programmes, did not result in a more reliable classification in the 2 projects in Bangladesh. The presence of clinical signs of lepromatous leprosy, more specifically nodules or diffuse infiltration, could be a useful addition to the classification criteria. If the sensitivity must remain higher than 90%, the lowest 'unconfirmed MB rate' obtainable in Bangladesh, using clinical criteria only, is 46.4%, for a sensitivity of 91.0%. However, the inclusion of skin-smear results in the classification criteria could improve the sensitivity to 96.6% and lower the 'unconfirmed MB rate' to 40.3%. A reduction in MB overclassification will result in more efficient and more cost-effective leprosy control programmes.

Treatment of multibacillary leprosy with a regimen of 13 weeks duration.

In a prospective study 559 multibacillary patients in Zaire were treated for 13 weeks with twice weekly rifampicin (600 mg) and daily ethionamide (500 mg) and dapsone (100 mg), 13-RED, or clofazimine (100 mg), 13-REC. The patients were followed for a total of 1418 person years, mean 3.2 years. The incidence of hepatitis was 3.3%. The incidence of relapses was 0.28 per 100 person years. Relapses were due to drug-sensitive organisms. In patients who received the same drug regimens but with a reduced dosage of ethionamide to 5 mg/k bodyweight, the incidence of hepatitis was significantly lower but the relapse rate was 7.8 per 100 person years of follow-up in the RED group, no relapses were diagnosed in the REC group. It is concluded that by the use of potent antileprosy drugs in suitable combinations and dosages, it will be possible to shorten the duration of antibacterial treatment in multibacillary leprosy to 3 months.

A controlled therapeutic trial in paucibacillary leprosy comparing a single dose of rifampicin with a single dose of rifampicin followed by one year of daily dapsone. The Collaborative Study Group for the Treatment of Leprosy in Zaire.

The cure rates of two treatment regimens in PB leprosy were compared in a prospective randomized trial: treatment U consisting of a single dose of rifampicin 40 mg/K bodyweight, and treatment A of rifampicin 1500 mg in a single dose, followed by one year of daily dapsone 100 mg. In patients with a BI = 0, the cure rates evaluated on the basis of histopathology of skin biopsies, were identical for the two regimens but in patients with a BI = 1, cure and relapse rates were unacceptable. For this reason and particularly the need to separate patients on the basis of the BI in skin biopsies, the single dose regimen does not appear to be suited for wide-scale application.

A longitudinal study of the incidence of leprosy in a hyperendemic area in Zaire, with special reference to PGL-antibody results. The Yalisombo Study Group.

Between 1984 and 1988, yearly surveys for leprosy were done among the 1500 people living in a previous leprosy segregation village in Zaire. In 1984 lepromin tests and phenolic glycolipid (PGL) antibody tests were done in a significant part of the population. The prevalence of the disease at that time was 16.1%, the proportion of multibacillary cases was 11.3% overall and 22% among active cases. Prior to 1984, 23% of paucibacillary cases and 56% of multibacillary cases had presented themselves spontaneously to the Leprosy Service. The exposure to the infection is uniform, but there is a suggestion of family clustering of cases. In spite of a rapidly bactericidal treatment of all known cases in 1984 and thereafter, the annual incidence of 0.34% did not decrease during the 4 years of the study. The PGL antibody test did not contribute to the diagnosis, classification or prognosis of the disease.

Combined regimens of one year duration in the treatment of multibacillary leprosy--I. Combined regimens with rifampicin administered during one year.

In 1981, 1982 and 1983, 216 multibacillary patients in Anjouan (Comores) and Burundi were treated for 8 weeks with daily rifampicin (600 mg) ethionamide (500 mg) and dapsone (100 mg) or clofazimine (100 mg) followed for 44 weeks by once weekly rifampicin (600 mg) and daily ethionamide (500 mg) and dapsone (100 mg) or clofazimine (100 mg). There were 109 previously untreated patients and 107 patients who had dapsone monotherapy, 16 of whom were infected with proven dapsone resistant Mycobacterium leprae. Clinical and bacteriological results were excellent but hepatotoxicity of this regimen remains a problem. No relapses were observed during a 2 to 6 years (mean: 4.29 years) follow-up period after the end of treatment (upper 95% confidence limit of 0.40 per 100 persons years). It is concluded that multibacillary leprosy can be successfully treated with a regimen of one year duration, but less toxic regimens, more easily applicable in the field, are necessary.

Combined regimens of one year duration in the treatment of multibacillary leprosy--II. Combined regimens with rifampicin administered during 6 months.

From 1981 to 1983 all multibacillary patients presenting at the collaborating centres in Zaire and Rwanda were treated with one of the following regimens: 6 months supervised daily RMP 600 mg, ETH 500 mg and DDS 100 mg or CLO 100 mg followed by 6 months unsupervised daily DDS 100 mg or CLO 100 mg with ETH 500 mg added or not. These regimens gave rise to hepatotoxicity, reversal and erythema nodosum leprosum reactions as described previously. Bactericidal activity was excellent. Among the 289 patients in the trial, with a mean follow-up period of 3.88 years, no relapses were observed, with an upper 95% confidence limit of 0.35 per 100 person years. Because of the hepatotoxicity, alternative short-course therapies need to be tested.

The incubation time of relapses after treatment of multibacillary leprosy with rifampicin containing regimens.

In order to determine the duration of follow-up needed to evaluate the efficacy of short-course bactericidal regimens for multibacillary leprosy, information is needed on the incubation time of relapses after stopping treatment. Several groups of patients, who had been on rifampicin-containing regimens, were followed up for periods ranging from 4 to 10 years. Two groups of relapses were observed: early relapses occurring within 3.5 years after stopping treatment, with a median incubation time of 1 year and 10 months (upper limit of 95% confidence interval: 2 years); and late relapses occurring more than 3.5 years after stopping treatment, with a median incubation of 5 years. Early relapses are probably due to insufficient treatment, and late relapses to persisting bacilli or to reinfection. It is concluded that the efficacy of short-course RMP-containing therapeutic regimens can be evaluated by observing the occurrence of early relapses, 50% of which occur before 2 years after the end of therapy.

Reasons for non-response during an ongoing leprosy survey in northern Zaire / ?

Low community response was observed during an ongoing leprosy incidence survey in an hyperendemic area in Northean Zaire. The reasons for the low response rate were investigated through interviews with 100 absentees. The following observations were made:1-The individuals in the sample had a poor understanding of the purpose of the survey;2-Persons known to have leprosy were of the opinion that the disease in incurable;3-There was general dissatisfaction with the way the survey was conducted. This was due to differences in perception between the survey team an the community. The findings are discussed, and recommendations are made to improve community participation

Prospective study on the relationship between intensive bactericidal therapy and leprosy reactions.

A systematic study was performed on the reactions occurring during several short-course therapy regimens for the treatment of paucibacillary and multibacillary patients. Most type 1 upgrading reactions in paucibacillary (PB) leprosy were mild to moderate and of short duration, while the time of onset was extremely variable. Their incidence was higher in the regimen rifampin (RMP) 900 mg once weekly for ten weeks than when a single dose of RMP 40 mg/kg body weight was given or 1500 mg in one dose followed by one year of dapsone (DDS) 100 mg daily. In multibacillary (MB) leprosy, three regimens were compared: MB-WHO regimen; regimen C, consisting of daily RMP 600 mg, ethionamide (ETH) 500 mg, and DDS or clofazimine (CLO) 100 mg for six months, followed by six months of daily DDS or CLO; and regimen D, identical to regimen C but comprising daily DDS or CLO plus ETH 500 mg during the second semester. Type 1 upgrading reactions occurred more frequently in MB patients and were more severe than in PB patients. They occurred more frequently and were more severe in regimens C and D than in the MB-WHO regimen. CLO 100 mg daily prevented type 1 reactions in MB patients and rendered them less severe. ENL was also more frequent in regimens C and D and was not prevented by CLO in the dosage used. Although there is some correlation between type 1 reactions and the total amount of RMP administered, other aspects of RMP administration.(ABSTRACT TRUNCATED AT 250 WORDS)