"As a patient I do not belong to the clinic, I belong to the community." Co-developing a multi-level, person-centred tuberculosis stigma intervention in Cape Town, South Africa.

Background: Anticipated, internal, and enacted stigma are major barriers to TB care engagement, and directly impact patient well-being. Unfortunately, targeted stigma interventions are lacking. We aimed to co-develop a person-centred stigma intervention with TB-affected community members and health workers in South Africa. Methods: Using a community-based participatory research approach, we conducted ten group discussions with people diagnosed with TB (past or present), caregivers, and health workers (total n=87) in Khayelitsha, Cape Town. Group discussions were facilitated by TB survivors. Discussion guides explored experiences and drivers of stigma and used human-centred design principles to co-develop solutions. Recordings were transcribed, coded, thematically analysed and then further interpreted using the socio-ecological model. Results: Intervention components across socio-ecological levels shared common behaviour change strategies, namely education, empowerment, engagement, and innovation. At the individual level, participants recommended counselling to improve TB knowledge and provide ongoing support. TB survivors can guide messaging to nurture stigma resilience by highlighting that TB can affect anyone and is curable, and provide lived experiences of TB to decrease internal stigma. At the interpersonal level, support clubs and family-centred counselling were suggested to dispel TB-related myths and foster support. At the institutional level, health worker stigma reduction training informed by TB survivor perspectives was recommended. Consideration of how integration of TB/HIV care services may exacerbate TB/HIV intersectional stigma and ideas for restructured service delivery models were suggested to decrease anticipated and enacted stigma. At the community level, participants recommended awareness-raising events led by TB survivors, including TB information in school curricula. At the policy level, solutions focused on reducing the visibility generated by a TB diagnosis and resultant stigma in health facilities and shifting tasks to community health workers. Conclusions: Decreasing TB stigma requires a multi-level approach. Co-developing a person-centred intervention with affected communities is feasible and generates stigma intervention components that are directed and implementable. Such community-informed intervention components should be prioritised by TB programs, including integrated TB/HIV care services.

The immune status of migrant populations in Europe and implications for vaccine-preventable disease control: a systematic review and meta-analysis.

BACKGROUND: Ensuring vaccination coverage reaches established herd immunity thresholds (HIT) is the cornerstone of any vaccination programme. Diverse migrant populations in European countries have been associated with cases of vaccine-preventable diseases (VPD) and outbreaks, yet it is not clear to what extent they are an under-immunised group. METHODS: We did a systematic review and meta-analysis to synthesise peer-reviewed published primary research reporting data on the immune status of migrants in EU/EEA countries, the UK and Switzerland, calculating their pooled immunity coverage for measles, mumps, rubella, and diphtheria using random-effects models. We searched on Web of Science, Embase, Global Health and MEDLINE (January 1st 2000 to June 10th 2022), with no language restrictions. The protocol is registered with PROSPERO (CRD42018103666). FINDINGS: Of 1103 abstracts screened, 62 met eligibility criteria, of which 39 were included in the meta-analysis. The meta-analysis included 75 089 migrants, predominantly from outside Europe. Pooled immunity coverage among migrant populations was well below the recommended HIT for diphtheria (n = 7, 57.4% [95% CI: 43.1-71.7%] I2 = 99% vs HIT 83-86%), measles (n = 21, 83.7% [95% CI: 79.2-88.2] I2 = 99% vs HIT 93-95%), and mumps (n = 8, 67.1% [95% CI: 50.6-83.6] I2 = 99% vs HIT 88-93%), and midway for rubella (n = 29, 85.6% [95% CI: 83.1-88.1%] I2 = 99% vs HIT 83-94%), with high heterogeneity across studies. INTERPRETATION: Migrants in Europe are an under-immunised group for a range of important VPDs, with this study reinforcing the importance of engaging children, adolescents, and adults in 'catch-up' vaccination initiatives on arrival for vaccines, doses, and boosters they may have missed in their home countries. Co-designing strategies to strengthen catch-up vaccination across the life-course in under-immunised groups is an important next step if we are to meet European and global targets for VPD elimination and control and ensure vaccine equity.

An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.

Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.

Clinicopathological profile of peritoneal tuberculosis and a new scoring model for predicting mortality: an international ID-IRI study.

Existing literature about peritoneal tuberculosis (TBP) is relatively insufficient. The majority of reports are from a single center and do not assess predictive factors for mortality. In this international study, we investigated the clinicopathological characteristics of a large series of patients with TBP and determined the key features associated with mortality. TBP patients detected between 2010 and 2022 in 38 medical centers in 13 countries were included in this retrospective cohort. Participating physicians filled out an online questionnaire to report study data. In this study, 208 patients with TBP were included. Mean age of TBP cases was 41.4 ± 17.5 years. One hundred six patients (50.9%) were females. Nineteen patients (9.1%) had HIV infection, 45 (21.6%) had diabetes mellitus, 30 (14.4%) had chronic renal failure, 12 (5.7%) had cirrhosis, 7 (3.3%) had malignancy, and 21 (10.1%) had a history of immunosuppressive medication use. A total of 34 (16.3%) patients died and death was attributable to TBP in all cases. A pioneer mortality predicting model was established and HIV positivity, cirrhosis, abdominal pain, weakness, nausea and vomiting, ascites, isolation of Mycobacterium tuberculosis in peritoneal biopsy samples, TB relapse, advanced age, high serum creatinine and ALT levels, and decreased duration of isoniazid use were significantly related with mortality (p < 0.05). This is the first international study on TBP and is the largest case series to date. We suggest that using the mortality predicting model will allow early identification of high-risk patients likely to die of TBP.

"This is an illness. No one is supposed to be treated badly": Community-based stigma assessments in South Africa to inform TB stigma intervention design.

Background: Though TB-related stigma is a recognized barrier to care, interventions are lacking and gaps remain in understanding the drivers and experiences of TB-related stigma. We undertook community-based mixed methods stigma assessments to inform stigma intervention design. Methods: We adapted the Stop TB Partnership stigma assessment tool, and trained three peer research associates (PRAs; two TB survivors, one community health worker) to conduct surveys with people with TB (PWTB, n=93) and caregivers of children with TB (n=24) at peri-urban and rural clinic sites in Khayelitsha, Western Cape, and Hammanskraal, Gauteng Province, South Africa. We descriptively analyzed responses for each stigma experience (anticipated, internal, and enacted), calculated stigma scores, and undertook generalized linear regression analysis. We further conducted 25 in-depth interviews with PWTB (n=22) and caregivers TB (n=3). Using inductive thematic analysis, we performed open coding to identify emergent themes, and selective coding to identify relevant quotes. Themes were organised using the CARD (Constraints, Actions, Risks and Desires) framework. Results: Surveys revealed at least one-third of PWTB and one-quarter of caregivers report experiences of anticipated, internal, and/or enacted stigma, which affected engagement throughout the care cascade. Participants in rural locations (compared to peri-urban) reported higher anticipated, internal, and enacted stigma (ß-coefficient 0.72, 0.71, and 0.74). Interview participants described how stigma experiences, including HIV intersectional stigma, act individually and in concert as key constraints to impede care, and underpins failure to disclose a TB diagnosis, isolation, and exclusion. Stigma resilience arose through understanding that TB can affect anyone and should not diminish self-worth. Risks of stigma, driven by fears related to disease severity and infectiousness, led to care disengagement and impaired psychological wellbeing. Participants desired counselling, identifying a specific role for TB survivors as peer counsellors, and community education. Conclusions: Stigma is highly prevalent and negatively impacts TB care and the well-being of PWTB, warranting its assessment as a primary outcome indicator rather than intermediary contributor to poor cascade outcomes. Multicomponent stigma interventions are needed, including counselling for PWTB and education for health workers and communities. Such interventions must incorporate contextual differences based on gender or setting, and use survivor-guided messaging to foster stigma resilience.

Prevention and treatment of infectious diseases in migrants in Europe in the era of universal health coverage.

Some subpopulations of migrants to Europe are generally healthier than the population of the country of settlement, but are at increased risk of key infectious diseases, including tuberculosis, HIV, and viral hepatitis, as well as under- immunisation. Infection screening programmes across Europe work in disease silos with a focus on individual diseases at the time of arrival. We argue that European health-care practitioners and policy makers would benefit from developing a framework of universal health care for migrants, which proactively offers early testing and vaccinations by delivering multi-disease testing and catch-up vaccination programmes integrated within existing health systems. Such interventions should be codeveloped with migrant populations to overcome barriers faced in accessing services. Aligning policies with the European Centre for Disease Prevention and Control guidance for health care for migrants, community-based preventive health-care programmes should be delivered as part of universal health care. However, effective implementation needs appropriate funding, and to be underpinned by high-quality evidence.

Country-specific approaches to latent tuberculosis screening targeting migrants in EU/EEA* countries: A survey of national experts, September 2019 to February 2020.

BackgroundMigrants in low tuberculosis (TB) incidence countries in the European Union (EU)/European Economic Area (EEA) are an at-risk group for latent tuberculosis infection (LTBI) and are increasingly included in LTBI screening programmes.AimTo investigate current approaches and implement LTBI screening in recently arrived migrants in the EU/EEA and Switzerland.MethodsAt least one TB expert working at a national level from the EU/EEA and one TB expert from Switzerland completed an electronic questionnaire. We used descriptive analyses to calculate percentages, and framework analysis to synthesise free-text responses.ResultsExperts from 32 countries were invited to participate (30 countries responded): 15 experts reported an LTBI screening programme targeting migrants in their country; five reported plans to implement one in the near future; and 10 reported having no programme. LTBI screening was predominantly for asylum seekers (n = 12) and refugees (n = 11). Twelve countries use 'country of origin' as the main eligibility criteria. The countries took similar approaches to diagnosis and treatment but different approaches to follow-up. Six experts reported that drop-out rates in migrants were higher compared with non-migrant groups. Most of the experts (n = 22) called for a renewed focus on expanding efforts to screen for LTBI in migrants arriving in low-incidence countries.ConclusionWe found a range of approaches to LTBI screening of migrants in the EU/EEA and Switzerland. Findings suggest a renewed focus is needed to expand and strengthen efforts to meaningfully include migrants in these programmes, in order to meet regional and global elimination targets for TB.

The relationship between mental health and risk of active tuberculosis: a systematic review.

OBJECTIVES: Tuberculosis (TB) and mental illnesses are highly prevalent globally and often coexist. While poor mental health is known to modulate immune function, whether mental disorders play a causal role in TB incidence is unknown. This systematic review examines the association between mental health and TB disease risk to inform clinical and public health measures. DESIGN: Systematic review, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. SEARCH STRATEGY AND SELECTION CRITERIA: MEDLINE, PsycINFO and PsycEXTRA databases were searched alongside reference list and citation searching. Inclusion criteria were original research studies published 1 January 1970-11 May 2020 reporting data on the association between mental health and TB risk. DATA EXTRACTION, APPRAISAL AND SYNTHESIS: Data were extracted on study design and setting, sample characteristics, measurement of mental illness and TB, and outcomes including effect size or prevalence. Studies were critically appraised using Critical Appraisal Skills Programme (CASP) and Appraisal Tool for Cross-Sectional Studies (AXIS) checklists. RESULTS: 1546 records published over 50 years were screened, resulting in 10 studies included reporting data from 607 184 individuals. Studies span across Asia, South America and Africa, and include mood and psychotic disorders. There is robust evidence from cohort studies in Asia demonstrating that depression and schizophrenia can increase risk of active TB, with effect estimates ranging from HR=1.15 (95% CI 1.03 to 1.28) to 2.63 (95% CI 1.74 to 3.96) for depression and HR=1.52 (95% CI 1.29 to 1.79) to RR=3.04 for schizophrenia. These data align with evidence from cross-sectional studies, for example, a large survey across low-income and middle-income countries (n=242 952) reports OR=3.68 (95% CI 3.01 to 4.50) for a depressive episode in those with TB symptoms versus those without. CONCLUSIONS: Individuals with mental illnesses including depression and schizophrenia experience increased TB incidence and represent a high-risk population to target for screening and treatment. Integrated care for mental health and TB is needed, and interventions tackling mental illnesses and underlying drivers may help reduce TB incidence globally. PROSPERO REGISTRATION NUMBER: CRD42019158071.

Migration and outbreaks of vaccine-preventable disease in Europe: a systematic review.

Migrant populations are one of several underimmunised groups in the EU or European Economic Area (EU/EEA), yet little is known about their involvement in outbreaks of vaccine-preventable diseases. This information is vital to develop targeted strategies to improve the health of diverse migrant communities. We did a systematic review (PROSPERO CRD42019157473; Jan 1, 2000, to May 22, 2020) adhering to PRISMA guidelines, to identify studies on vaccine-preventable disease outbreaks (measles, mumps, rubella, diphtheria, pertussis, polio, hepatitis A, varicella, Neisseria meningitidis, and Haemophilus influenzae) involving migrants residing in the EU/EEA and Switzerland. We identified 45 studies, reporting on 47 distinct vaccine-preventable disease outbreaks across 13 countries. Most reported outbreaks involving migrants were of measles (n=24; 6496 cases), followed by varicella (n=11; 505 cases), hepatitis A (n=7; 1356 cases), rubella (n=3; 487 cases), and mumps (n=2; 293 cases). 19 (40%) outbreaks, predominantly varicella and measles, were reported in temporary refugee camps or shelters. Of 11 varicella outbreaks, nine (82%) were associated with adult migrants. Half of measles outbreaks (n=11) were associated with migrants from eastern European countries. In conclusion, migrants are involved in vaccine-preventable disease outbreaks in Europe, with adult and child refugees residing in shelters or temporary camps at particular risk, alongside specific nationality groups. Vulnerability varies by disease, setting, and demographics, highlighting the importance of tailoring catch-up vaccination interventions to specific groups in order to meet regional and global vaccination targets as recommended by the new Immunisation Agenda 2030 framework for action. A better understanding of vaccine access and intent in migrant groups and a greater focus on co-designing interventions is urgently needed, with direct implications for COVID-19 vaccine delivery.

Participatory approaches in the development of health interventions for migrants: a systematic review.

OBJECTIVE: Analysis of participatory approaches to developing health interventions for migrants and how approaches embody core participatory principles of inclusivity and democracy. DESIGN: A systematic review of original articles. Electronic searches within the databases MEDLINE, Embase, Global Health and PsychINFO (from inception-November 2020). ELIGIBILITY CRITERIA FOR STUDY SELECTION: Original peer-reviewed articles reporting research to develop and implement a health intervention for migrants, incorporating participatory approaches. We defined migrants as foreign-born individuals. Only articles reporting the full research cycle (inception, design, implementation, analysis, evaluation, dissemination) were included. DATA EXTRACTION: We extracted information related to who was involved in research (migrants or other non-academic stakeholders), the research stage at which they were involved (inception, design, implementation, analysis, evaluation, dissemination), the method of their involvement and how this aligned with the core principles of participatory research-categorising studies as exhibiting active or pseudo (including proxy and indirect) participation. RESULTS: 1793 publications were screened, of which 28 were included in our analysis. We found substantial variation in the application of participatory approaches in designing health interventions targeting migrants: across 168 individual research stages analysed across the 28 studies, we recorded 46 instances of active participation of migrants, 30 instances of proxy participation and 24 instances of indirect participation. All studies involved non-academic stakeholders in at least one stage of the research, only two studies exhibited evidence of active participation of migrants across all research stages. Evidence is limited due to the variability of terms and approaches used. CONCLUSIONS: Important shortfalls in the meaningful inclusion of migrants in developing health interventions exist, suggesting a more rigorous and standardised approach is warranted to better define and deliver participatory research and improve quality. REGISTRATION: This review followed Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines and is registered on the Open Science Framework (osf.io/2bnz5).

Initiation and completion of treatment for latent tuberculosis infection in migrants globally: a systematic review and meta-analysis.

BACKGROUND: Latent tuberculosis infection (LTBI) is one of the most prevalent infections globally and can lead to the development of active tuberculosis disease. In many low-burden countries, LTBI is concentrated within migrant populations often because of a higher disease burden in the migrant's country of origin. National programmes consequently focus on screening and treating LTBI in migrants to prevent future tuberculosis cases; however, how effective these programmes are is unclear. We aimed to assess LTBI treatment initiation and outcomes among migrants, and the factors that influence both. METHODS: For this systematic review and meta-analysis, we searched Embase, MEDLINE, and Global Health, and manually searched grey literature from Jan 1, 2000, to April 21, 2020. We included primary research articles reporting on LTBI treatment initiation or completion, or both, in migrants and excluded articles in which data were not stratified by migrant status, or in which the data were related to outcomes before 2000. There were no geographical or language restrictions. All included studies were quality appraised using recognised tools depending on their design, and we assessed the heterogeneity of analyses using I2. We extracted data on the numbers of migrants initiating and completing treatment. Our primary outcomes were LTBI treatment initiation and completion in migrants (defined as foreign-born). We used random-effects meta-regression to examine the influence of factors related to these outcomes. The study is registered with PROSPERO (CRD42019140338). FINDINGS: 2199 publications were retrieved screened, after which 39 publications from 13 mostly high-income, low-burden countries were included in our analyses, with treatment initiation and completion data reported for 31 598 migrants positive for LTBI, with not all articles reporting the full pathway from initiation to completion. The pooled estimate for the true proportion of migrants testing positive who initiated treatment was 69% (95% CI 51-84; I2= 99·62%; 4409 of 8764). The pooled estimate for the true proportion of migrants on treatment in datasets, who subsequently completed it was 74% (95% CI = 66-81; I2= 99·19%; 15 516 of 25 629). Where data were provided for the entire treatment pathway, the pooled estimate for the true proportion of migrants who initiated and completed treatment after a positive test was only 52% (95% CI 40-64; I2= 98·90%; 3289 of 6652). Meta-regression showed that LTBI programmes are improving, with more recent reported data (2010-20) associated with better rates of treatment initiation and completion, with multiple complex factors affecting treatment outcomes in migrants. INTERPRETATION: Although our analysis highlights that LTBI treatment initiation and completion in migrants has improved considerably from 2010-20, there is still room for improvement, with drop out reported along the entire treatment pathway. The delivery of these screening and treatment programmes will require further strengthening if the targets to eradicate tuberculosis in low-incidence countries are to be met, with greater focus needed on engaging migrants more effectively in the clinic and understanding the diverse and unique barriers and facilitators to migrants initiating and completing treatment. FUNDING: European Society of Clinical Microbiology and Infectious Diseases, the Rosetrees Trust, the National Institute for Health Research, and the Academy of Medical Sciences.

Platelet Activation and the Immune Response to Tuberculosis.

In 2019 10 million people developed symptomatic tuberculosis (TB) disease and 1.2 million died. In active TB the inflammatory response causes tissue destruction, which leads to both acute morbidity and mortality. Tissue destruction in TB is driven by host innate immunity and mediated via enzymes, chiefly matrix metalloproteinases (MMPs) which are secreted by leukocytes and stromal cells and degrade the extracellular matrix. Here we review the growing evidence implicating platelets in TB immunopathology. TB patients typically have high platelet counts, which correlate with disease severity, and a hypercoagulable profile. Platelets are present in human TB granulomas and platelet-associated gene transcripts are increased in TB patients versus healthy controls. Platelets most likely drive TB immunopathology through their effect on other immune cells, particularly monocytes, to lead to upregulation of activation markers, increased MMP secretion, and enhanced phagocytosis. Finally, we consider current evidence supporting use of targeted anti-platelet agents in the treatment of TB due to growing interest in developing host-directed therapies to limit tissue damage and improve treatment outcomes. In summary, platelets are implicated in TB disease and contribute to MMP-mediated tissue damage via their cellular interactions with other leukocytes, and are potential targets for novel host-directed therapies.

Doxycycline host-directed therapy in human pulmonary tuberculosis.

BACKGROUNDMatrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODSThirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTSWhole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov NCT02774993.FUNDINGSingapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.

Neutrophil-Mediated Immunopathology and Matrix Metalloproteinases in Central Nervous System - Tuberculosis.

Tuberculosis (TB) remains one of the leading infectious killers in the world, infecting approximately a quarter of the world's population with the causative organism Mycobacterium tuberculosis (M. tb). Central nervous system tuberculosis (CNS-TB) is the most severe form of TB, with high mortality and residual neurological sequelae even with effective TB treatment. In CNS-TB, recruited neutrophils infiltrate into the brain to carry out its antimicrobial functions of degranulation, phagocytosis and NETosis. However, neutrophils also mediate inflammation, tissue destruction and immunopathology in the CNS. Neutrophils release key mediators including matrix metalloproteinase (MMPs) which degrade brain extracellular matrix (ECM), tumor necrosis factor (TNF)-α which may drive inflammation, reactive oxygen species (ROS) that drive cellular necrosis and neutrophil extracellular traps (NETs), interacting with platelets to form thrombi that may lead to ischemic stroke. Host-directed therapies (HDTs) targeting these key mediators are potentially exciting, but currently remain of unproven effectiveness. This article reviews the key role of neutrophils and neutrophil-derived mediators in driving CNS-TB immunopathology.

Extrapulmonary tuberculosis among migrants in Europe, 1995 to 2017.

OBJECTIVES: The proportion of tuberculosis (TB) cases occurring in migrants in Europe is increasing. Extrapulmonary TB poses challenges in diagnosis and treatment and causes serious morbidity and mortality, yet its extent in migrant populations is unclear. We assessed patterns of extrapulmonary TB in migrants across the European Union (EU)/European Free Trade Association (EFTA). We investigated the proportion of extrapulmonary TB cases among migrants versus non-migrants, and variations by specific site of disease, reporting European region, and migrant region of origin. METHODS: We carried out a cross-sectional secondary database analysis, utilizing 23 years of data collected between 1995 and 2017 from the European Surveillance System of the European Centre for Disease Prevention and Control for 32 EU/EFTA countries. RESULTS: In total, 1 270 896 TB cases were included, comprising 326 987 migrants (25.7%) and 943 909 non-migrants (74.3%). Of TB cases among migrants, 45.2% (n = 147 814) were extrapulmonary compared to 21.7% (n = 204 613) among non-migrants (p < 0.001). Lymphatic, bone/joint and peritoneal/digestive TB were more common among migrant than non-migrant extrapulmonary cases. A lower proportion of extrapulmonary TB was seen in Eastern Europe (17.4%, n = 98 656 of 566 170) and Southern Europe (29.6%, n = 62 481 of 210 828) compared with Western (35.7%, n = 89 498 of 250 517) and Northern Europe (41.8%, n = 101 792 of 243 381). Migrants from South-East Asia and Sub-Saharan Africa were at highest risk of extrapulmonary disease, with 62.0% (n = 55 401 of 89 353) and 54.5% (n = 38 327 of 70 378) of cases, respectively, being extrapulmonary. CONCLUSIONS: Among TB cases in the EU/EFTA, extrapulmonary disease is significantly more common in migrants than in non-migrants. There is a need to improve clinical awareness of extrapulmonary TB and to integrate its detection into screening programmes.

"It's a life you're playing with": A qualitative study on experiences of NHS maternity services among undocumented migrant women in England.

BACKGROUND: Undocumented migrant women experience complex barriers to maternity services, are less likely to receive the recommended level of maternity care, and have poorer obstetric outcomes than non-migrant women. There are concerns increasing restrictions on entitlement to health services have a detrimental impact on access to services and obstetric outcomes, particularly among undocumented migrant women. The study aimed to investigate the experiences of undocumented migrant women who have been pregnant in England, and factors affecting access to care and health outcomes. METHODS: We conducted in-depth semi-structured interviews June-December 2017 with a purposive sample of migrant women born outside the UK (aged>18) who had experiences of pregnancy and undocumented status (without permission to reside) in the UK, recruited through Doctors of the World (DOTW) UK. Interpreting services were used on request. Interviews were recorded, transcribed, and analysed using thematic analysis. Ethical approval: Imperial College London Research Ethics Committee (ICREC reference: 17IC3924). RESULTS: Semi-structured interviews were conducted with 20 participants, 10 of whom had their first antenatal appointment after the national target of 13 weeks, and nine of whom reported complications. Themes defining women's experiences of pregnancy included: restricted agency, intersecting stressors, and an ongoing cycle of precarity, defined by legal status, social isolation, and economic status. CONCLUSIONS: This study provides new evidence of women's experiences of pregnancy in the UK in the context of increasingly restrictive health policies including charging and data sharing. Six recommendations are made to ensure the UK and other migrant receiving countries work towards reducing inequalities and achieving national and global targets for maternal and child health and universal health coverage.

Translating scientific discoveries during pandemics: ensuring equity for people affected by COVID-19 and tuberculosis.

The #COVID19 pandemic has emphasised major global health inequities: this editorial argues lessons learnt from TB must remind us of the gaps in the research agenda that must be addressed to ensure that scientific advances are equitably disseminated https://bit.ly/3bTZHS3.

Epidemic and pandemic viral infections: impact on tuberculosis and the lung: A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases Study Group for Mycobacterial Infections (ESGMYC).

Major epidemics, including some that qualify as pandemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV, influenza A (H1N1)pdm/09 and most recently COVID-19, affect the lung. Tuberculosis (TB) remains the top infectious disease killer, but apart from syndemic TB/HIV little is known regarding the interaction of viral epidemics and pandemics with TB. The aim of this consensus-based document is to describe the effects of viral infections resulting in epidemics and pandemics that affect the lung (MERS, SARS, HIV, influenza A (H1N1)pdm/09 and COVID-19) and their interactions with TB. A search of the scientific literature was performed. A writing committee of international experts including the European Centre for Disease Prevention and Control Public Health Emergency (ECDC PHE) team, the World Association for Infectious Diseases and Immunological Disorders (WAidid), the Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC) was established. Consensus was achieved after multiple rounds of revisions between the writing committee and a larger expert group. A Delphi process involving the core group of authors (excluding the ECDC PHE team) identified the areas requiring review/consensus, followed by a second round to refine the definitive consensus elements. The epidemiology and immunology of these viral infections and their interactions with TB are discussed with implications for diagnosis, treatment and prevention of airborne infections (infection control, viral containment and workplace safety). This consensus document represents a rapid and comprehensive summary on what is known on the topic.

Long-term risk of tuberculosis among migrants according to migrant status: a cohort study.

BACKGROUND: The majority of tuberculosis (TB) cases in low-incidence countries occur in migrants. Only few studies have assessed the long-term TB risk in migrants after immigration, and datasets have not considered this across a range of diverse migrant groups. This nationwide study aimed to investigate long-term TB risk among migrants according to migrant status and region of origin. METHODS: This cohort study included all migrants aged ≥ 18 years who obtained residence in Denmark from 1993 to 2015, with a mean follow-up of 10.8 years [standard deviation (SD) 7.3]. Migrants were categorized based on legal status of residence and region of origin. Incidence rates (IR) and rate ratios (IRR) were estimated by Poisson regression. RESULTS: A total of 142 314 migrants were included. Across all migrants, the TB risk was highest during year 1 of residence (IR 275/100 000 person-years; 95% CI 249-305) followed by a gradual decline, though TB risk remained high for over a decade. Compared with the Danish-born population, the IRRs after 7-8 years were particularly higher among former asylum seekers (IRR 31; 95% CI 20-46), quota refugees (IRR 31; 95% CI 16-71), and family-reunified with refugees (IRR 22; 95% CI 12-44). Sub-Saharan African migrants also experienced elevated risk (IRR 75; 95% CI 51-109). The proportion of migrants with pulmonary TB was 52.4%. CONCLUSION: All migrant groups experienced an initial high TB risk, but long-term risk remained high in key migrant groups. Most European countries focus TB screening on or soon after arrival. Our study suggests that approaches to TB screening should be adapted, with migrant populations benefiting from long-term access to preventive health services.

Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus-associated Tuberculosis.

BACKGROUND: Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with human immunodeficiency virus (HIV) infection (PLWH). PLWH with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence antiretroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. We investigated the hypothesis that invariant natural killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS. METHODS: In a cross-sectional study of 101 PLWH and HIV-uninfected South African patients with active TB and controls, iNKT cells were enumerated using α-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterized by flow cytometry. In a second study of 49 people with HIV type 1 (HIV-1) and active TB commencing antiretroviral therapy, iNKT cells in TB-IRIS patients and non-IRIS controls were compared longitudinally. RESULTS: Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in patients with HIV-1 infection and active TB was associated with development of TB-IRIS following antiretroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8- subset depleted and degranulated around the time of TB-IRIS onset. CONCLUSIONS: Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality toward cytotoxicity. Increased CD4- cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS.