WHO target product profiles for TB preventive treatment.

BACKGROUND: The WHO has developed target product profiles (TPPs) describing the most appropriate qualities for future TPT regimens to assist developers in aligning the characteristics of new treatments with programmatic requirements.METHODS: A technical consultation group was convened by the WHO to determine regimen attributes with greatest potential impact for patients (i.e., improved risk/benefit profile) and populations (i.e., reduction in transmission and TB prevalence). The group categorised regimen attributes as 'priority´ or 'desirable´; and defined for each attribute the minimum requirements and optimal targets.RESULTS: Nine priority attributes were defined, including efficacy, treatment duration, safety, drug-drug interactions, barrier to emergence of drug resistance, target population, formulation, dosage, frequency and route of administration, stability and shelf life. Regimens meeting optimal targets were characterised, for example, as having superior efficacy, treatment duration of ≤2 weeks, and improved tolerability and safety profile compared with current regimens. The four desirable attributes included regimen cost, safety in special populations, treatment adherence and need for drug susceptibility testing in the index patient.DISCUSSION: It may be difficult for a single regimen to satisfy all characteristics so regimen developers may have to consider trade-offs. Additional operational aspects may be relevant to the feasibility and public health impact of new TPT regimens.

TB preventive treatment in high- and intermediate-incidence countries: research needs for scale-up.

BACKGROUND: In 2018, the WHO Member States committed to providing TB preventive treatment (TPT) to at least 30 million people by 2022. However, only 6.3 million people had initiated TPT by the end of 2019. Major knowledge gaps and research needs in diagnosis, treatment and the programmatic management of TPT (PMTPT) require to be addressed urgently.METHODS: In September 2019, a group of stakeholders involved in PMTPT in high TB burden countries met to develop an action agenda to support the global expansion of PMTPT.RESULTS: Barriers at the health system level, and priorities for research to overcome these, were identified for each step of the PMTPT cascade. The need for data on TPT financing, gaps and coverage under national health insurance schemes, as well as the need for mathematical and cost-effectiveness modelling of the impact of TPT on TB incidence and mortality were highlighted. Specific research needs were identified for high-risk populations such as household contacts of any age and people living with HIV, as well as other people at risk.CONCLUSIONS: The meeting facilitated agreement on a set of actions needed to ensure that PMTPT continues to expand to achieve the End TB Strategy targets.

Initial default from tuberculosis treatment: how often does it happen and what are the reasons?

A study in 11 primary health care facilities in and around Cape Town determined the proportion of bacteriologically confirmed tuberculosis (TB) cases who did not start treatment (initial default) and identified reasons for it. Databases from centralised laboratories were compared with electronic TB treatment registers. Fourteen per cent (373/2758) of TB suspects were TB cases. Of the 58 (16%) initial defaulters, 14 (24%) died, while 26 (45%) could not be interviewed for address-related reasons. The 18 subjects who were interviewed indicated reasons for initial default that were (56%) or were not (44%) directly linked to services. High initial default rates require improvement in the quality of health services.

From suspect to patient: tuberculosis diagnosis and treatment initiation in health facilities in South Africa.

SETTING: Thirteen primary health care (PHC) facilities in the Stellenbosch District, South Africa. OBJECTIVE: To assess the use of a sputum register to evaluate the tuberculosis (TB) diagnostic process and the initiation of TB treatment in selected PHC facilities in a country with a centralised laboratory system. DESIGN: This prospective study was conducted between April 2004 and March 2005. The names of all individuals submitting sputum samples for TB testing were noted in a newly introduced sputum register. We classified all TB suspects with two positive smears as TB cases and consulted TB treatment registers until 3 months after sputum submission to determine how many had started treatment. RESULTS: A total of 4062 persons aged > or =15 years submitted sputum samples, of whom 2484 were TB suspects. There were 2037 suspects with at least two results, 367 (18%) had at least two positive smears and 64 (17%) of these did not start treatment (initial defaulters). Over the entire diagnostic process, up to 5% of TB cases were missed, and up to 26% did not start treatment and were not reported. CONCLUSION: By correcting diagnostic weaknesses identified in the sputum register, PHC facilities will be able to detect, treat and cure a higher percentage of TB patients.

An evaluation of symptom and chest radiographic screening in tuberculosis prevalence surveys.

SETTING: A tuberculosis (TB) prevalence survey was performed in 2002 in two urban communities in Cape Town, South Africa. The population was 36,334 in 2001, and the TB notification rate was 341 per 100,000 population for new smear-positive TB in 2002. OBJECTIVE: To evaluate the relative contributions of symptom and chest radiographic (CXR) screening in the detection of subjects with smear- and/or culture-positive TB in prevalence surveys. DESIGN: Information on symptoms, CXR abnormalities, sputum smear and culture was gathered from a random cluster sample of 1170 adults (aged > or = 15 years). Smear and/or culture-positive TB was used as the gold standard. RESULTS: Of 1170 adults, 29 had bacteriologically positive TB (smear- and/or culture-positive). The presence of any abnormalities on CXR had the highest sensitivity for detecting subjects with bacteriologically positive TB (0.97, 95%CI 0.90-1.00). Specificity for any abnormalities on CXR was 0.67 (95%CI 0.64-0.70). The specificity of any of five TB-related symptoms was 0.68 (95%CI 0.65-0.71). Individual symptoms had low sensitivities, ranging from 0.10 for fever to 0.54 for cough of > or = 2 weeks. CONCLUSION: In this TB prevalence survey, CXR screening, but not symptom screening, was a sensitive alternative to sputum examination of all participants.

Rifampicin resistance after treatment for latent tuberculous infection: a systematic review and meta-analysis.

SETTING: Treatment for latent tuberculous infection (LTBI) reduces the risk of tuberculosis (TB) disease. Shorter, rifamycin-containing regimens have been shown to be as effective as 6 months of isoniazid and superior with regard to safety and completion rate. It is unknown whether preventive therapy with rifamycins increases resistance to the drugs used. OBJECTIVE: To determine whether treatment for LTBI with rifamycin-containing regimens leads to significant development of resistance against rifamycins. DESIGN: Systematic review and meta-analysis. RESULTS: We included six randomised-controlled trials of rifamycin-containing regimens for LTBI treatment that reported drug resistance. There was no statistically significant increased risk of rifamycin resistance after LTBI treatment with rifamycin-containing regimens compared to non-rifamycin-containing regimens (RR 3.45, 95%CI 0.72-16.56; P = 0.12) or placebo (RR 0.20, 95%CI 0.02-1.66; P = 0.13). CONCLUSION: Preventive treatment with rifamycin-containing regimens does not significantly increase rifamycin resistance. Programmatic management of LTBI requires the creation of sound surveillance systems to monitor drug resistance.

Development and evaluation of a new chest radiograph reading and recording system for epidemiological surveys of tuberculosis and lung disease.

OBJECTIVE: The development and evaluation of a new chest radiograph reading and recording system (CRRS) for community surveys of tuberculosis (TB) and lung disease. DESIGN: An experienced pulmonologist read 2608 chest X-rays (CXRs) performed as part of a TB prevalence survey using the newly developed CRRS. The kappa (kappa) for inter-reader agreement was calculated after a second reader reported on a stratified random sample of 810 (31%) of the 2608 CXRs. The kappa for intra-reader agreement was calculated from the repeated reporting of a stratified random sample of 104 CXRs. RESULTS: The kappa agreement between the two readers was 0.69 (95%CI 0.64-0.74) for abnormalities consistent with TB and 0.47 (95%CI 0.42-0.53) for any abnormalities. The kappa for intra-reader agreement was 0.90 (95%CI 0.81-0.99) for abnormalities consistent with TB and 0.85 (95%CI 0.74-0.95) for any abnormalities. CONCLUSION: This standardised method for CXR reading and recording provides satisfactory inter- and intra-reader agreement, making it suitable for surveys of TB and other forms of lung disease in the community. Its use will permit comparisons of results obtained in different surveys.

Impact of mycobacterial culture among HIV-infected adults with presumed TB in Uganda: a prospective cohort study.

BACKGROUND: Implementation of new tuberculosis (TB) diagnostic strategies in resource-constrained settings is challenging. We measured the impact of solid and liquid mycobacterial cultures on treatment practices for patients undergoing TB evaluation in Kampala, Uganda. METHODS: We enrolled consecutive smear-negative, human immunodeficiency virus positive adults with cough of ⩾2 weeks from September 2009 to April 2010. Laboratory technicians performed mycobacterial cultures on solid and liquid media. We compared empiric treatment decisions with solid and liquid culture in terms of diagnostic yield and time to results, and assessed impact on patient management. RESULTS: Of 200 patients enrolled, 26 (13%) had culture-confirmed TB: 22 (85%) on solid culture alone, 2 (8%) on liquid culture alone, and 2 (8%) on both solid and liquid culture. Thirty-four patients received empiric anti-tuberculosis treatment, but only 10 (29%) were culture-positive. Median time to a positive result on solid culture was 92 days (interquartile range [IQR] 69-148) compared to 106 days (IQR 66-157) for liquid culture. No patients initiated treatment following a positive result on liquid culture. CONCLUSION: The introduction of mycobacterial culture did not influence care for patients undergoing evaluation for TB in Kampala, Uganda. Attention to contextual factors surrounding implementation is needed to ensure the effective introduction of new testing strategies in low-income countries.

Contexte : La mise en œuvre de nouvelles stratégies de diagnostic de la tuberculose (TB) dans les contextes de ressources limitées constitue un défi. Nous avons mesuré l'impact des cultures mycobactériennes en milieu solide et liquide sur les pratiques de traitement des patients ayant une évaluation de la TB à Kampala, Ouganda.Méthodes : Nous avons enrôlé des patients adultes consécutifs à frottis négatif, positifs pour le virus de l'immunodéficience humaine avec toux de ⩾2 semaines, de septembre 2009 à avril 2010. Les techniciens de laboratoire ont réalisé des cultures mycobactériennes en milieu solide et liquide. Nous avons comparé les décisions de traitement empirique aux cultures en milieu solide et liquide en termes de rendement diagnostique et de délai d'obtention des résultats et nous avons évalué l'impact sur la gestion des patients.Résultats : Des 200 patients enrôlés, 26 (13%) avaient une TB confirmée par culture, 22 (85%) par culture en milieu solide seule, 2 (8%) par culture en milieu liquide seul et 2 (8%) par culture à la fois en milieu solide et liquide. Trente-quatre patients ont reçu un traitement de TB empirique, mais seulement 10 (29%) ont eu une TB à culture positive. Le délai médian d'obtention d'un résultat de culture positive en milieu solide a été de 92 jours (IQR 69­148). Le délai médian d'obtention d'un résultat de culture positive en milieu liquide a été de 106 jours (IQR 66­157). Aucun patient n'a commencé un traitement à la suite d'un résultat de culture positive en milieu liquide.Conclusion : L'introduction de la culture mycobactérienne n'a pas influencé les soins aux patients bénéficiant d'une évaluation de TB à Kampala, Ouganda. Il est nécessaire d'être attentif aux facteurs contextuels entourant la mise en œuvre afin d'assurer une introduction effective de nouvelles stratégies de tests dans les pays à faible revenu.

Marco de referencia: La ejecución de nuevas estrategias de diagnóstico de la tuberculosis (TB) en los entornos con limitación de recursos es problemática. En el presente estudio se midió la repercusión del uso del cultivo de micobacterias en medio sólido o liquido sobre las prácticas de tratamiento de los pacientes en curso de investigación diagnóstica de la TB en Kampala, Uganda.Métodos: Se incluyeron de manera consecutiva en el estudio los pacientes adultos, seronegativos frente al virus de la inmunodeficiencia humana, que consultaban por tos de ⩾2 semanas de duración y presentaban baciloscopia negativa, de septiembre del 2009 a abril del 2010. Los auxiliares de laboratorio practicaron el cultivo de micobacterias en medio sólido y medio líquido. Se compararon las decisiones empíricas de tratamiento y los tipos de cultivo, con respecto al rendimiento diagnóstico y al lapso hasta obtener los resultados y se evaluó su repercusión en el manejo de los pacientes.Resultados: De los 200 pacientes que participaron en el estudio, 26 obtuvieron confirmación del diagnóstico de TB mediante el cultivo (13%), 22 de ellos con el cultivo en medio sólido únicamente (85%), dos con el cultivo en medio líquido exclusivamente y dos con ambos tipos de cultivo (8%). Treinta y cuatro pacientes recibieron tratamiento antituberculoso empírico, pero solo 10 de ellos obtuvieron un cultivo positivo (29%). La mediana del lapso hasta obtener el resultado del cultivo en medio sólido fue 92 días (IQR 69­148). La mediana de este lapso con los cultivos en medio líquido fue 106 días (IQR 66­157). Ningún paciente inició el tratamiento antituberculoso después de haber obtenido el resultado positivo del cultivo en medio líquido.Conclusión: La introducción del cultivo para micobacterias no tiene ninguna influencia en la atención que reciben los pacientes en quienes se investiga la TB en Kampala, Uganda. Es importante prestar atención a los factores contextuales que rodean la ejecución, a fin de lograr una introducción eficaz de las nuevas estrategias diagnósticas en los países con recursos limitados.

[Doubling of the number of cases of tick bites and lyme borreliosis seen by general practitioners in the Netherlands]. / Verdubbeling van het aantal consulten voor tekenbeten en Lyme-borreliose in de huisartsenpraktijk in Nederland.

OBJECTIVE: To obtain detailed information about the current geographical distribution and incidence of tick bites and Lyme borreliosis in the Netherlands and to identify regional differences in the ecological risk factors that might be involved. DESIGN: Retrospective questionnaire study. SETTING: All Dutch general practitioner's (GP) practices. METHODS: In April 2002, all GPs in the Netherlands were asked to complete a short questionnaire on the number of cases of tick bites and erythema migrans seen in 2001 and the size of their practice. Associations with possible risk factors were determined at the municipal level. Results were compared with the results of a similar study done in 1995. RESULTS: The response of the GPs was 64.5% (4730/7330). Together, all GPs reported seeing approximately 61,000 patients in 2001 with tick bites and 12,000 patients with erythema migrans. The incidence of erythema migrans was estimated at 73 per 100,000 inhabitants. There were obvious risk areas. At the municipal level, tick bites and erythema migrans were positively associated with the area covered by forest, sandy soil, the number of roe deer and tourism. There was a negative association with the degree of urbanisation. Increases in tourism in areas with many ticks, new forests in urban regions and an increased number of horses were positively associated with the increase in tick bites and erythema migrans since 1994. CONCLUSION: The number of patients with tick bites and erythema migrans seen by GPs in the Netherlands had doubled between 1994 and 2001. This increase may be attributed partly to changes in ecological risk factors and human behaviour. The number of cases of Lyme borreliosis may be reduced by giving prophylactic information annually about ticks and ways to remove them, plus additional education of patients about the recognition of erythema migrans.

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

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

Comparison of symptoms and treatment outcomes between actively and passively detected tuberculosis cases: the additional value of active case finding.

Passive detection of tuberculosis (TB) cases may lead to delay in treatment which may contribute to increased severity of disease and mortality. Active case finding may be an alternative. In a community survey in Cape Town, South Africa, we actively detected 27 bacteriologically positive TB cases and compared those with 473 passively detected TB cases. Seven of 27 (26%) actively detected TB cases did not start treatment within 2 months and were considered initial defaulters. Those who did start treatment had similar treatment success rates as passively detected TB cases (both 80%) (OR 1.01, CI 0.33-3.09). Passively detected cases reported the presence of the symptoms cough (OR 3.72, 95% CI 1.47-9.39), haemoptysis (OR 3.20, 95% CI 1.03-9.93), night sweats (OR 3.35, 95% CI 1.40-7.99), fever (OR 4.28, 95% CI 1.21-15.14), and weight loss (OR 11.14, 95% CI 4.17-29.74) more often than those detected actively. We conclude that although TB cases detected by a community survey are less symptomatic and are prone to a high initial default rate, active case finding can potentially identify a substantial portion of the existing caseload at an earlier stage of disease, thereby reducing the risk of transmission.

Association between smoking and tuberculosis infection: a population survey in a high tuberculosis incidence area.

BACKGROUND: Associations between smoking and tuberculosis disease including death from tuberculosis have been reported, but there are few reports on the influence of smoking on the risk of developing Mycobacterium tuberculosis infection. The aim of this study was to determine the association between smoking and M tuberculosis infection. METHODS: In a cross sectional population survey, data on smoking and tuberculin skin test (TST) results of 2401 adults aged > or =15 years were compared. RESULTS: A total of 1832 (76%) subjects had a positive TST (> or = 10 mm induration). Of 1309 current smokers or ex-smokers, 1070 (82%) had a positive TST. This was significantly higher than for never smokers (unadjusted OR 1.99, 95% confidence interval (CI) 1.62 to 2.45). A positive relationship with pack-years was observed, with those smoking more than 15 pack-years having the highest risk (adjusted OR 1.90, 95% CI 1.28 to 2.81). CONCLUSION: Smoking may increase the risk of M tuberculosis infection.