Summary Background Tuberculosis elimination in countries with a low incidence of the disease necessitates multiple interventions, including innovations in migrant screening. We examined a cohort of ...migrants screened for tuberculosis before entry to England, Wales, and Northern Ireland and tracked the development of disease in this group after arrival. Methods As part of a pilot pre-entry screening programme for tuberculosis in 15 countries with a high incidence of the disease, the International Organization for Migration screened all applicants for UK visas aged 11 years or older who intended to stay for more than 6 months. Applicants underwent a chest radiograph, and any with results suggestive of tuberculosis underwent sputum testing and culture testing (when available). We tracked the development of tuberculosis in those who tested negative for the disease and subsequently migrated to England, Wales, and Northern Ireland with the Enhanced Tuberculosis Surveillance system. Primary outcomes were cases of all forms of tuberculosis (including clinically diagnosed cases), and bacteriologically confirmed pulmonary tuberculosis. Findings Our study cohort was 519 955 migrants who were screened for tuberculosis before entry to the UK between Jan 1, 2006, and Dec 31, 2012. Cases notified on the Enhanced Tuberculosis Surveillance system between Jan 1, 2006, and Dec 31, 2013, were included. 1873 incident cases of all forms of tuberculosis were identified, and, on the basis of data for England, Wales, and Northern Ireland, the estimated incidence of all forms of tuberculosis in migrants screened before entry was 147 per 100 000 person-years (95% CI 140–154). The estimated incidence of bacteriologically confirmed pulmonary tuberculosis in migrants screened before entry was 49 per 100 000 person-years (95% CI 45–53). Migrants whose chest radiographs were compatible with active tuberculosis but with negative pre-entry microbiological results were at increased risk of tuberculosis compared with those with no radiographic abnormalities (incidence rate ratio 3·2, 95% CI 2·8–3·7; p<0·0001). Incidence of tuberculosis after migration increased significantly with increasing WHO-estimated prevalence of tuberculosis in migrants' countries of origin. 35 of 318 983 pre-entry screened migrants included in a secondary analysis with typing data were assumed index cases. Estimates of the rate of assumed reactivation tuberculosis ranged from 46 (95% CI 42–52) to 91 (82–102) per 100 000 population. Interpretation Migrants from countries with a high incidence of tuberculosis screened before being granted entry to low-incidence countries pose a negligible risk of onward transmission but are at increased risk of tuberculosis, which could potentially be prevented through identification and treatment of latent infection in close collaboration with a pre-entry screening programme. Funding Wellcome Trust, UK National Institute for Health Research, UK Medical Research Council, Public Health England, and Department of Health Policy Research Programme.
Summary Background An increasing number of countries with low incidence of tuberculosis have pre-entry screening programmes for migrants. We present the first estimates of the prevalence of and risk ...factors for tuberculosis in migrants from 15 high-incidence countries screened before entry to the UK. Methods We did a population-based cross-sectional study of applicants for long-term visas who were screened for tuberculosis before entry to the UK in a pilot programme between Oct 1, 2005, and Dec 31, 2013. The primary outcome was prevalence of bacteriologically confirmed tuberculosis. We used Poisson regression to estimate crude prevalence and created a multivariable logistic regression model to identify risk factors for the primary outcome. Findings 476 455 visa applicants were screened, and the crude prevalence of bacteriologically confirmed tuberculosis was 92 (95% CI 84–101) per 100 000 individuals. After adjustment for age and sex, factors that were strongly associated with an increased risk of bacteriologically confirmed disease at pre-entry screening were self-report of close or household contact with an individual with tuberculosis (odds ratio 11·6, 95% CI 7·0–19·3; p<0·0001) and being an applicant for settlement and dependant visas (1·3, 1·0–1·6; p=0·0203). Interpretation Migrants reporting contact with an individual with tuberculosis had the highest risk of tuberculosis at pre-entry screening. To tackle this disease burden in migrants, a comprehensive and collaborative approach is needed between countries with pre-entry screening programmes, health services in the countries of origin and migration, national tuberculosis control programmes, and international public health bodies. Funding Wellcome Trust, Medical Research Council, and UK National Institute for Health Research.
What is the evidence base for the effectiveness of interventions to reduce tuberculosis (TB) incidence in countries which have low TB incidence?
We conducted a systematic review of interventions for ...TB control and prevention relevant to low TB incidence settings (<10 cases per 100 000 population). Our analysis was stratified according to "direct" or "indirect" effects on TB incidence. Review quality was assessed using AMSTAR2 criteria. We summarised the strength of review level evidence for interventions as "sufficient", "tentative", "insufficient" or "no" using a framework based on the consistency of evidence within and between reviews.
We found sufficient review level evidence for direct effects on TB incidence/case prevention of vaccination and treatment of latent TB infection. We also found sufficient evidence of beneficial indirect effects attributable to drug susceptibility testing and adverse indirect effects (measured as sub-optimal treatment outcomes) in relation to use of standardised first-line drug regimens for isoniazid-resistant TB and intermittent dosing regimens. We found insufficient review level evidence for direct or indirect effects of interventions in other areas, including screening, adherence, multidrug-resistant TB, and healthcare-associated infection.
Our review has shown a need for stronger evidence to support expert opinion and country experience when formulating TB control policy.
Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such ...countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population.
We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System.
Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166–182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio IRR 1·49, 95% CI 1·33–1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62–0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59–3·38; p<0·0001).
Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants.
National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre.
In low-incidence countries, tuberculosis mainly affects migrants, mostly resulting from reactivation of latent tuberculosis infection (LTBI) acquired in high-incidence countries before migration. A ...nationwide primary care-based LTBI testing and treatment programme for migrants from high-incidence countries was therefore established in high tuberculosis incidence areas in England. We aimed to assess the effectiveness of this programme.
We did a retrospective, population-based cohort study of migrants who registered in primary care between Jan 1, 2011, and Dec 31, 2018, in 55 high-burden areas with programmatic LTBI testing and treatment. Eligible individuals were aged 16–35 years, born in a high-incidence country, and had entered England in the past 5 years. Individuals who tested interferon-γ release assay (IGRA)-negative were advised about symptoms of tuberculosis, whereas those who tested IGRA-positive were clinically assessed to rule out active tuberculosis and offered preventive therapy. The primary outcome was incident tuberculosis notified to the national Enhanced Tuberculosis Surveillance system.
Our cohort comprised 368 097 eligible individuals who had registered in primary care, of whom 37 268 (10·1%) were tested by the programme. 1446 incident cases of tuberculosis were identified: 166 cases in individuals who had IGRA testing (incidence 204 cases 95% CI 176–238 per 100 000 person-years) and 1280 in individuals without IGRA testing (82 cases 77–86 per 100 000 person-years). Overall, in our primary analysis including all diagnosed tuberculosis cases, a time-varying association was identified between LTBI testing and treatment and lower risk of incident tuberculosis (hazard ratio HR 0·76 95% CI 0·63–0·91) when compared with no testing. In stratified analysis by follow-up period, the intervention was associated with higher risk of tuberculosis diagnosis during the first 6 months of follow-up (9·93 7·63–12·9) and a lower risk after 6 months (0·57 0·41–0·79). IGRA-positive individuals had higher risk of tuberculosis diagnosis than IGRA-negative individuals (31·9 20·4–49·8). Of 37 268 migrants who were tested, 6640 (17·8%) were IGRA-positive, of whom 1740 (26·2%) started preventive treatment. LTBI treatment lowered the risk of tuberculosis: of 135 incident cases in the IGRA-positive cohort, seven cases were diagnosed in the treated group (1·87 cases 95% CI 0·89–3·93 per 1000 person-years) and 128 cases were diagnosed in the untreated group (10·9 cases 9·16–12·9 per 1000 person-years; HR 0·14 95% CI 0·06–0·32).
A low proportion of eligible migrants were tested by the programme and a small proportion of those testing positive started treatment. Despite this, programmatic LTBI testing and treatment of individuals migrating to a low-incidence region is effective at diagnosing active tuberculosis earlier and lowers the long-term risk of progression to tuberculosis. Increasing programme participation and treatment rates for those testing positive could substantially impact national tuberculosis incidence.
National Institute for Health Research Health Protection Research Unit in Respiratory Infections.
In 2017, 15.6% of the people living in England were born abroad, yet we have a limited understanding of their use of health services and subsequent health conditions. This linked population-based ...cohort study aims to describe the hospital-based healthcare and mortality outcomes of 1.5 million non-European Union (EU) migrants and refugees in England.
We will link four data sources: first, non-EU migrant tuberculosis pre-entry screening data; second, refugee pre-entry health assessment data; third, national hospital episode statistics; and fourth, Office of National Statistics death records. Using this linked dataset, we will then generate a population-based cohort to examine hospital-based events and mortality outcomes in England between Jan 1, 2006, and Dec 31, 2017. We will compare outcomes across three groups in our analyses: 1) non-EU international migrants, 2) refugees, and 3) general population of England.
We will obtain approval to use unconsented patient identifiable data from the Secretary of State for Health through the Confidentiality Advisory Group and the National Health Service Research Ethics Committee. After data linkage, we will destroy identifying data and undertake all analyses using the pseudonymised dataset. The results will provide policy makers and civil society with detailed information about the health needs of non-EU international migrants and refugees in England.
Background Tuberculosis elimination in countries with a low incidence of the disease necessitates multiple interventions, including innovations in migrant screening. We examined a cohort of migrants ...screened for tuberculosis before entry to England, Wales, and Northern Ireland and tracked the development of disease in this group after arrival. Methods As part of a pilot pre-entry screening programme for tuberculosis in 15 countries with a high incidence of the disease, the International Organization for Migration screened all applicants for UK visas aged 11 years or older who intended to stay for more than 6 months. Applicants underwent a chest radiograph, and any with results suggestive of tuberculosis underwent sputum testing and culture testing (when available). We tracked the development of tuberculosis in those who tested negative for the disease and subsequently migrated to England, Wales, and Northern Ireland with the Enhanced Tuberculosis Surveillance system. Primary outcomes were cases of all forms of tuberculosis (including clinically diagnosed cases), and bacteriologically confirmed pulmonary tuberculosis. Findings Our study cohort was 519955 migrants who were screened for tuberculosis before entry to the UK between Jan 1, 2006, and Dec 31, 2012. Cases notified on the Enhanced Tuberculosis Surveillance system between Jan 1, 2006, and Dec 31, 2013, were included. 1873 incident cases of all forms of tuberculosis were identified, and, on the basis of data for England, Wales, and Northern Ireland, the estimated incidence of all forms of tuberculosis in migrants screened before entry was 147 per 100000 person-years (95% CI 140-154). The estimated incidence of bacteriologically confirmed pulmonary tuberculosis in migrants screened before entry was 49 per 100000 person-years (95% CI 45-53). Migrants whose chest radiographs were compatible with active tuberculosis but with negative pre-entry microbiological results were at increased risk of tuberculosis compared with those with no radiographic abnormalities (incidence rate ratio 3.2, 95% CI 2.8-3.7; p<0.0001). Incidence of tuberculosis after migration increased significantly with increasing WHO-estimated prevalence of tuberculosis in migrants' countries of origin. 35 of 318983 pre-entry screened migrants included in a secondary analysis with typing data were assumed index cases. Estimates of the rate of assumed reactivation tuberculosis ranged from 46 (95% CI 42-52) to 91 (82-102) per 100000 population. Interpretation Migrants from countries with a high incidence of tuberculosis screened before being granted entry to low-incidence countries pose a negligible risk of onward transmission but are at increased risk of tuberculosis, which could potentially be prevented through identification and treatment of latent infection in close collaboration with a pre-entry screening programme. Funding Wellcome Trust, UK National Institute for Health Research, UK Medical Research Council, Public Health England, and Department of Health Policy Research Programme.
In red cells from normal individuals (HbA cells), the K+-Cl- cotransporter (KCC) is inactivated by low O2 tension whilst in those from sickle cell patients (HbS cells), it remains fully active. ...Changes in free intracellular Mg2+ have been proposed as a mechanism. In HbA cells, KCC activity was stimulated by Mg2+ depletion and inhibited by Mg2+ loading but the effect of O2 was independent of Mg2+. At all Mg2+is, the transporter was stimulated in oxygenated cells, minimally active in deoxygenated ones. By contrast, the stimulatory effects of O2 was abolished by inhibitors of protein (de)phosphorylation. HbS cells had elevated KCC activity, which was of similar magnitude in oxygenated and deoxygenated cells, regardless of Mg2+ clamping. In deoxygenated cells, the antisickling agent dimethyl adipimidate inhibited sickling, Psickle and KCC. Results indicate a role for protein phosphorylation in O2 dependence of KCC, with different activities of the relevant enzymes in HbA and HbS cells, probably dependent on Hb.
We compare the effects of 1-chloro-2,4-dinitrobenzene (CDNB) and phenazine methosulphate (PMS) on Gardos channel activity in normal human red cells. Both stimulate channel activity, both are ...dependent on the presence of extracellular Ca
2+, and neither is affected by inhibitors of protein (de)phosphorylation. Of the two, PMS has a considerably greater effect. In addition, a major difference is that whilst CDNB has a greater stimulatory effect in oxygenated cells, by contrast, PMS is more effective in deoxygenated cells. These actions are correlated with ca. 30% inhibition of the plasma membrane Ca
2+ pump (PMCA) and an increased sensitivity of the Gardos channel to Ca
2+ (EC
50 falling to about 150 nM). These findings are important in understanding how oxidants alter red cell cation permeability and may be relevant to the abnormal permeability phenotype shown by deoxygenated sickle cells.
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