2022 TB programme review in Pakistan: strengthening governance, with better patient diagnosis and treatment.

BACKGROUND: In Pakistan, 84% of healthcare is provided by the private sector. We conducted an epidemiological and programme review for TB to document progress and guide further efforts. METHODS: Surveillance and data systems were assessed before analysing epidemiological data. We reviewed the programme at federal, provincial and peripheral levels and compiled national data along with WHO estimates to describe the evolution of epidemiological and programme indicators. RESULTS: In 2021, of the estimated number of TB cases, 55% of overall cases and 18% of drug-resistant cases were diagnosed and treated respectively. The contribution of the private sector in case detection increased from 30% in 2017 to 40% by 2021. For newly diagnosed pulmonary TB cases, the overall proportion of confirmed cases was 52%. In 2021, testing for rifampicin resistance among confirmed cases was 66% for new and 84% for previously treated patients. The treatment success rate exceeded 90% for drug susceptible TB. The main challenges identified were a funding gap (60% in 2021-2023), fragmented electronic systems for data collection and suboptimal coordination among provinces. CONCLUSIONS: The main challenges prevent further progress in controlling TB. By addressing these, Pakistan could improve coverage of interventions, including diagnosis and treatment. Bacteriological confirmation using recommended diagnostics also requires further optimisation.

CONTEXTE: Au Pakistan, le secteur privé assure 84% des services de santé. Une étude épidémiologique et programmatique a été réalisée sur la TB afin de recueillir des informations sur les avancées réalisées et de guider les actions à venir. MÉTHODES: Les systèmes de surveillance et de données ont été évalués préalablement à l'analyse des données épidémiologiques. Nous avons examiné le programme aux niveaux fédéral, provincial et local et compilé les données nationales ainsi que les estimations de l'OMS afin de décrire l'évolution des indicateurs épidémiologiques et du programme. RÉSULTATS: En 2021, environ 55% de l'ensemble cas de TB et 18% des cas résistants aux médicaments ont été diagnostiqués et traités respectivement. La contribution du secteur privé dans la détection des cas est passée de 30% en 2017 à 40% en 2021. La proportion totale de cas confirmés pour les nouveaux diagnostics de TB pulmonaire s'élevait à 52%. En 2021, les tests de résistance à la rifampicine parmi les cas confirmés s'élevaient à 66% pour les nouveaux patients et de 84% pour les patients déjà traités. Le taux de réussite du traitement a dépassé 90% pour la TB sensible aux médicaments. Les défis majeurs comprennent un manque de financement (60% pour la période 2021­2023), des systèmes électroniques de collecte de données fragmentés et une coordination insuffisante entre les provinces. CONCLUSIONS: Les défis majeurs entravent les avancées dans la lutte contre la TB. En les mettant en évidence, le Pakistan pourrait améliorer la portée des interventions, y compris le diagnostic et le traitement. Il est également essentiel d'optimiser la confirmation bactériologique en utilisant les diagnostics recommandés.

Commitment, partnerships and operational research: three priorities for 11 EMR countries to achieve TB elimination.

BACKGROUND: In 2022, 11 of 22 Member States of the WHO Eastern Mediterranean Region (EMR) had an estimated TB incidence of <20 cases per 100,000 population. We assessed preparedness for elimination and provided recommendations to pursue the process. METHODS: We surveyed 11 EMR national TB programme managers and collected information on eight TB elimination framework domains using a close-ended data collection tool. We compiled, consolidated and validated data, including a virtual consultation before triangulating data with other sources. RESULTS: Implementation was sufficient (≥74%) for 5 of 8 domains, highest for TB infection management, TB preventive treatment, laboratory service, drug management, drug-resistant TB and TB-HIV collaboration (89%, 83% and 78%, respectively). Countries ranked lowest for commitment (73%), operational research and infection control (63%), and partnership/collaborations (41%). Five countries reached >80% when consolidating the responses, reaching sufficient from all domains. Two reached <50%. CONCLUSION: Key identified obstacles to TB elimination in EMR were insufficient commitment/financing, sub-optimal partnerships/collaborations and operational research calling for 1) all-stakeholder-inclusive, sustainably funded TB elimination plans, 2) cost-effective tools to exchange strategic information and build operational research capacity, and 3) improved collaboration.

CONTEXTE: En 2022, 11 des 22 États membres de la Région de la Méditerranée orientale de l'OMS avaient une incidence de la TB estimée à moins de 20 cas pour 100 000 habitants. Nous avons évalué l'état de préparation à l'élimination et formulé des recommandations pour poursuivre le processus. MÉTHODES: Nous avons interrogé 11 responsables de programmes nationaux de lutte contre la TB dans la région de la Méditerranée orientale et recueilli des informations sur huit domaines du cadre d'élimination de la TB à l'aide d'un outil de collecte de données à questions fermées. Nous avons compilé, consolidé et validé les données, y compris lors d'une consultation virtuelle, avant de les trianguler avec d'autres sources. RÉSULTATS: La mise en œuvre était suffisante (≥74%) pour 5 des 8 domaines, les plus élevés étant la gestion de l'infection tuberculeuse, le traitement préventif de la TB, les services de laboratoire, la gestion des médicaments, la TB pharmacorésistante et la collaboration TB-VIH (89%, 83% et 78%, respectivement). Les pays se sont classés au dernier rang pour l'engagement (73%), la recherche opérationnelle et la lutte contre l'infection (63%) et le partenariat/la collaboration (41%). Cinq pays ont atteint >80% lors de la consolidation des réponses, atteignant un niveau suffisant dans tous les domaines. Deux pays ont atteint un taux de réponse inférieur à 50%. CONCLUSION: Les principaux obstacles à l'élimination de la TB dans les pays de l'Union européenne sont un engagement/un financement insuffisant, des partenariats/collaborations sous-optimaux et une recherche opérationnelle nécessitant 1) des plans d'élimination de la TB incluant toutes les parties prenantes et bénéficiant d'un financement durable, 2) des outils rentables permettant d'échanger des informations stratégiques et de renforcer les capacités de recherche opérationnelle, et 3) une meilleure collaboration.

Vaccination in post-tuberculosis lung disease management: A review of the evidence.

INTRODUCTION AND OBJECTIVES: Post-tuberculosis lung disease (PTLD), as other chronic respiratory disorders, may have infectious complications; some of them can be prevented with vaccinations. So far, no document has discussed the potential role of vaccination in PTLD. Therefore, the objective of this review was to describe vaccination recommendations to prevent infections potentially capable of complicating PTLD. MATERIALS AND METHODS: A non-systematic review of the literature was conducted. The following keywords were used: tuberculosis, vaccination, vaccines and PTLD. PubMed/MEDLINE and Embase were used as the search engine, focusing on English-language literature only. RESULTS: We identified 9 vaccines potentially useful in PTLD. Influenza, pneumococcal and anti-COVID-19 vaccinations should be recommended. Patients with PTLD can also benefit from vaccination against shingles. Vaccination against pertussis is mainly relevant during childhood. Diphtheria, tetanus and measles vaccination are recommended for general population and should be considered in patients with PTLD not previously vaccinated. Tdap (Tetanus, diphtheria, and pertussis) booster should be repeated in every adult every ten years. Vaccination against BCG retains its importance during early childhood in countries where TB is endemic. CONCLUSIONS: Vaccination deserves to be considered among the strategies to prevent and/or mitigate PTLD complications. Further evidence is necessary to better understand which vaccines have the greatest impact and cost-benefit.

A systematic review of the costs of diagnosis for multidrug-resistant/extensively drug-resistant TB in different settings.

BACKGROUND: We performed an analysis of the cost and relative merits of different strategies for the diagnosis of multidrug-resistant/extensively drug-resistant TB (MDR/XDR-TB) in different settings.METHODS: We systematically reviewed the published evidence on cost/cost-effectiveness of rapid MDR/pre-XDR-TB and other methods for XDR-TB testing up to September 2022. PRISMA guidelines were followed. Collected data were analysed using Stata v17 software. Cost data were reported in USD ($) and summarised by mean, standard deviation, and range. Country income level was defined according to the World Bank country classification. Three simplified scenarios were also used to explore testing implications, based on low, intermediate and high TB incidence.RESULTS: Of 157 records, 25 studies were included with 24 reporting the cost of Xpert/RIF and two that evaluated the implementation of the MTBDRplus test. The total rapid test cost ranged from $12.41-$218, including $1.13-$74.60 for reagents/consumables and $0.40-$14.34 for equipment.CONCLUSION: The cost of MDR/XDR-TB diagnostics is lower in low resource settings. However, the cost-effective implementation of MDR/XDR-TB diagnostic algorithms requires careful consideration of local resources to avoid missed identification and the use of inappropriate regimen.

Management of childhood MDR-TB in Europe and Central Asia: report of a Regional WHO meeting.

BACKGROUND: As the WHO European Region has the highest proportion of multidrug-resistant TB (MDR-TB) among total incident TB cases, many children and adolescents are at risk of MDR-TB infection and disease.METHODS: We performed an electronic survey of clinicians and TB programme personnel who attended the 2020 Regional Consultation on child and adolescent TB organised by the WHO Regional Office. We characterised access to diagnostics and drugs, and practices in the prevention and management of child and adolescent MDR-TB.RESULTS: Children and adolescents are inconsistently represented in national guidelines and budgets; child-friendly drug formulations for MDR-TB treatment are insufficiently available in 57% of countries, and 32% of countries reported paediatric drug stock-outs. The novel drugs, bedaquiline and delamanid, are accessible by respectively 80% and 60% of respondent countries. Respondents were asked how many children were diagnosed with MDR-TB in 2019, and a comparison of this number to modelled estimates of incidence (to identify the case detection gap) and WHO notifications (to identify the case reporting gap) showed substantial differences in both comparisons.CONCLUSIONS: Better representation of this patient group in guidelines and budgets, greater access to drugs and improved reporting are essential to reach TB elimination in this Region.

Tuberculosis, COVID-19 and migrants: Preliminary analysis of deaths occurring in 69 patients from two cohorts.

Little is known about the relationship between the COVID-19 and tuberculosis (TB). The aim of this study is to describe a group of patients who died with TB (active disease or sequelae) and COVID-19 in two cohorts. Data from 49 consecutive cases in 8 countries (cohort A) and 20 hospitalised patients with TB and COVID-19 (cohort B) were analysed and patients who died were described. Demographic and clinical variables were retrospectively collected, including co-morbidities and risk factors for TB and COVID-19 mortality. Overall, 8 out of 69 (11.6%) patients died, 7 from cohort A (14.3%) and one from cohort B (5%). Out of 69 patients 43 were migrants, 26/49 (53.1%) in cohort A and 17/20 (85.0%) in cohort B. Migrants: (1) were younger than natives; in cohort A the median (IQR) age was 40 (27-49) VS. 66 (46-70) years, whereas in cohort B 37 (27-46) VS. 48 (47-60) years; (2) had a lower mortality rate than natives (1/43, 2.3% versus 7/26, 26.9%; p-value: 0.002); (3) had fewer co-morbidities than natives (23/43, 53.5% versus 5/26-19.2%) natives; p-value: 0.005). The study findings show that: (1) mortality is likely to occur in elderly patients with co-morbidities; (2) TB might not be a major determinant of mortality and (3) migrants had lower mortality, probably because of their younger age and lower number of co-morbidities. However, in settings where advanced forms of TB frequently occur and are caused by drug-resistant strains of M. tuberculosis, higher mortality rates can be expected in young individuals.

Tuberculosis surveillance in adolescents: what to learn from European Union/European Economic Area data?

OBJECTIVE: To describe tuberculosis (TB) characteristics in the adolescent 10-19 years age group that is often underrepresented in surveillance and studies despite the high global TB burden estimated for this group.SETTING AND DESIGN: We use the case-based data reported to the European Surveillance System (TESSy) from European Union (EU)/European Economic Area (EEA) countries between 2007 and 2016 to describe notification rates, TB characteristics and treatment outcomes among adolescent TB cases. We also compare TB characteristics in young adolescents (10-14 years) and older adolescents (15-19 years).RESULTS: For the period 2007 to 2016, 705 826 TB cases were reported to TESSy by 29 EU/EEA countries, 38 054 (5.4%) of which were adolescents. The overall EU/EEA notification rate among adolescents was 6.9 per 100 000 population, 3.5 among young adolescents and 10.1 among older adolescents. The two adolescent groups had differences regarding sex distribution, site of disease, sputum smear microscopy positivity, laboratory confirmation and treatment outcome.CONCLUSION: Younger and older adolescents should be analysed as separate groups when studying and reporting TB, particularly to inform better targeting of TB prevention and care interventions in the future, in order to improve outcomes.

People- and patient-centred care for tuberculosis: models of care for tuberculosis.

SETTING: The first pillar in the World Health Organisation's (WHO's) End TB strategy is 'Integrated, patient-centred tuberculosis (TB) care and prevention'. However, what are patient- and people-centred care, and why are they important for TB care and prevention? OBJECTIVE AND RATIONALE: To define the concept of patient-centred care, the rationale for it, and its evolution into people-centred care; and to explore evidence on whether people-centred approaches work for TB and present key areas where continuous efforts are needed to support their implementation. RESULTS: Based on the reasoning and the evidence presented, we propose four areas where further action is needed to ensure that people-centred TB care and prevention can achieve their potential: 1) reaching consensus on definitions and terminology; 2) strengthening research; 3) using and evaluating new technology; and 4) nurturing country leadership and advocacy. CONCLUSION: Integrated, people-centred TB care and prevention should be a guiding light for all those involved in the quest to eliminate TB. However, much still needs to be done to bridge the gaps between the potential and actual performance of national programmes.

Differentiating characteristics of deafblindness and autism in people with congenital deafblindness and profound intellectual disability.

BACKGROUND: In persons with deafblindness, it is hard to distinguish autism spectrum disorders from several deafblind specific behaviours caused by the dual sensory impairments, especially when these persons are also intellectually disabled. As a result, there is an over-diagnosis of autism in persons who are deafblind leading to unsuitable interventions. METHODS: Autism as specified by the DSM-IV was studied in 10 persons with congenital deafblindness with profound intellectual disabilities. Behaviours of people with deafblindness and autism (n = 5) and of people with deafblindness without autism (n = 5) were observed in a semi-standardised assessment. RESULTS: All people with deafblindness showed impairments in social interaction, communication and language. In contrast to persons without autism, people with deafblindness and autism showed significantly more impairments in reciprocity of social interaction, quality of initiatives to contact and the use of adequate communicative signals and functions. No differences between the groups were found for quantity and persistence of stereotyped behaviour, quality of play and exploration and adequate problem-solving strategies. CONCLUSIONS: This study indicates that there are some possibilities to differentiate autism from behaviours specific for deafblindness. It also confirms the large overlap in overt behaviours between people with deafblindness and persons with autism.

Differential regulation of hyaluronic acid synthase isoforms in human saphenous vein smooth muscle cells: possible implications for vein graft stenosis.

Autologous saphenous vein bypass grafts (SVG) are frequently compromised by neointimal thickening and subsequent atherosclerosis eventually leading to graft failure. Hyaluronic acid (HA) generated by smooth muscle cells (SMC) is thought to augment the progression of atherosclerosis. The aim of the present study was (1) to investigate HA accumulation in native and explanted arterialized SVG, (2) to identify factors that regulate HA synthase (HAS) expression and HA synthesis, and (3) to study the function of the HAS2 isoform. In native SVG, expression of all 3 HAS isoforms was detected by RT-PCR. Histochemistry revealed that native and arterialized human saphenous vein segments were characterized by marked deposition of HA in association with SMC. Interestingly, in contrast to native SVG, cyclooxygenase (COX)-2 expression by SMC and macrophages was detected only in arterialized SVG. In vitro in human venous SMC HAS isoforms were found to be differentially regulated. HAS2, HAS1, and HA synthesis were strongly induced by vasodilatory prostaglandins via Gs-coupled prostaglandin receptors. In addition, thrombin induced HAS2 via activation of PAR1 and interleukin 1beta was the only factor that induced HAS3. By small interfering RNA against HAS2, it was shown that HAS2 mediated HA synthesis is critically involved in cell cycle progression through G1/S phase and SMC proliferation. In conclusion, the present study shows that HA-rich extracellular matrix is maintained after arterialization of vein grafts and might contribute to graft failure because of its proproliferative function in venous SMC. Furthermore, COX-2-dependent prostaglandins may play a key role in the regulation of HA synthesis in arterialized vein grafts.

Immunotherapy through TCR gene transfer.

The antigen specificity of T lymphocytes is dictated solely by the T cell receptor (TCR) alpha and beta chains. Consequently, genetic transfer of TCR chains may be an appealing strategy with which to impose a desirable virus- or tumor-antigen specificity onto cytotoxic or helper T cell populations. We describe here the genetic introduction of a virus-specific TCR into peripheral T cells in a mouse model system. These experiments showed that T cells redirected by TCR gene transfer expanded upon viral infection of mice and efficiently homed to effector sites. In this setting, TCR gene transfer was not associated with any significant autoimmune pathology. In addition, small numbers of TCR-transduced T cells promoted the rejection of antigen-expressing tumors in vivo. These data suggest that the redirection of T cells by TCR gene transfer is a viable strategy for the rapid induction of virus- or tumor-specific immunity.

Changing T cell specificity by retroviral T cell receptor display.

The diversity of the T cell receptor (TCR) repertoire is limited, because of the processes of positive and negative T cell selection. To obtain T cells with specificities beyond the immune system's capacity, we have developed a strategy for retroviral TCR display. In this approach, a library of T cell variants is generated in vitro and introduced into a TCR-negative murine T cell line by retroviral transfer. We document the value of TCR display by the creation of a library of an influenza A-specific TCR and the subsequent in vitro selection of TCRs that either recognize the parental influenza epitope or that have acquired a specificity for a different influenza A strain. The resulting in vitro selected TCRs induce efficient T cell activation after ligand recognition and are of equal or higher potency than the in vivo generated parent receptor. TCR display should prove a useful strategy for the generation of high-affinity tumor-specific TCRs for gene transfer purposes.

The influence of a fish oil-enriched diet on the phospholipid fatty acid turnover in the rabbit red cell membrane in vivo.

The influence of the polyunsaturated fatty acid (PUFA) composition of the diet on the rate of fatty acid turnover of individual phospholipids in the erythrocyte membrane in vivo was studied. Following modification of the fatty acid composition of the membrane phospholipids by the use of a fish oil or a linoleic acid enriched diet, phospholipids--labelled in the unsaturated fatty acid at the 2-position of the glycerol moiety--were introduced into the membrane of freshly isolated rabbit erythrocytes. Thereafter, the labelled erythrocytes were reinjected into the bloodstream of the animal. It appears that, with the exception of 1-palmitoyl,2-linoleoyl phosphatidylcholine, all other phosphatidylcholines disappear faster from the erythrocytes of fish oil-fed rabbits than from the red cells of linoleic acid-fed rabbits. Another parameter, which possibly influences the turnover rates of PUFA containing phospholipids, can be peroxidation. An attempt was made to measure peroxidative damage of lipids in vivo by the introduction of 1-palmitoyl,2-cis-parinaroyl phosphatidylcholine (PnPC)--a probe to measure oxidative stress--into the membrane of freshly isolated erythrocytes, in the same way as is described for the radioactive phospholipids. The data demonstrate that the fluorescent signal from the PnPC decreases at a fast rate which is independent of the dietary conditions.

Comparison of the effects of dietary vitamin E on in vivo and in vitro parameters of lipid peroxidation in the rabbit.

This study has investigated the effect of dietary vitamin E on markers of antioxidant status. Four groups of rabbits received diets containing 30 energy percent (en%) total fat (7.8 en% contributed by linoleic acid) for 12 weeks. D,1-alpha tocopheryl acetate was added to the diets to obtain a range of vitamin E concentrations (49, 114, 179, or 775 tocopherol equivalents per kg diet). Increased vitamin E concentrations were demonstrated in plasma lipoproteins and erythrocyte membranes following supplementation, and dietary effects on lipid peroxidation were investigated by (i) monitoring a fluorescent parinaric acid probe incorporated into erythrocyte membranes in vivo, (ii) determination of malondialdehyde and oxysterols in plasma, and (iii) investigation of the susceptibility of low density lipoprotein (LDL) to copper-induced conjugated diene formation in vitro. No effects of vitamin E were observed on parinaric acid oxidation in vivo or on the accumulation of lipid peroxidation products in plasma, but the resistance of LDL to oxidation in vitro increased significantly as vitamin E was supplemented to the diets. Our results demonstrate that under these dietary conditions (7.8 en% linoleic acid) increasing the vitamin E content of plasma and erythrocytes approximately two-fold does not reduce the level of lipid peroxidation in vivo, indicating sufficient antioxidant capacity on the lowest vitamin E diet. In contrast, LDL became more resistant to an extreme oxidative stress applied in vitro. The relevance of these assays to currently proposed mechanisms of atherosclerosis is discussed.

In vivo turnover of 1,2-dipalmitoylphosphatidylcholine and sphingomyelin in rabbit erythrocytes.

The in vivo turnover of both 1,2-dipalmitoylphosphatidylcholine (DPPC) and sphingomyelin (SM) in rabbit erythrocytes was studied. DPPC, either 14C-labelled in the fatty acyl chain at the 2-position of the glycerol moiety or 3H-labelled in the choline's methyl group, and [N-methyl-14C]SM (bovine) were introduced into the membrane of freshly isolated rabbit erythrocytes by using phospholipid transfer proteins. Thereafter, the labelled erythrocytes were reinjected into the bloodstream of the animal. Analysis of blood samples shows that both labels disappear from the circulating cells with the same rate, resulting in a half-time value of about 6.4-6.6 days. This result demonstrates that the loss of DPPC from the cells is due to transfer of intact molecules to the plasma and that a deacylation process is of no or minor importance as mechanism of renewal of DPPC. Labelled sphingomyelin, introduced into the rabbit erythrocyte membrane in a similar way, disappears from the circulating red cell with a half-time value of 15.5 days. This accounts for a daily replacement of the total SM pool by 3.2%.