Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study.

BACKGROUND: Little is known about how long the BCG vaccine protects against tuberculosis. We assessed the long-term vaccine effectiveness (VE) in Norwegian-born individuals. METHODS: In this retrospective population-based cohort study, we studied Norwegian-born individuals aged 12-50 years who were tuberculin skin test (TST) negative and eligible for BCG vaccination as part of the last round of Norway's mandatory mass tuberculosis screening and BCG vaccination programme between 1962 and 1975. We excluded individuals who had tuberculosis before or in the year of screening and those with unknown TST and BCG status. We obtained TST and BCG information and linked it to the National Tuberculosis Register, population and housing censuses, and the population register for emigrations and deaths. We followed individuals up to their first tuberculosis episode, emigration, death, or Dec 31, 2011. We used Cox regressions to estimate VE against all tuberculosis and just pulmonary tuberculosis by time since vaccination, adjusted for age, time, county-level tuberculosis rates, and demographic and socioeconomic indicators. FINDINGS: Median follow-up was 41 years (IQR 32-49) for 83 421 BCG-unvaccinated and 44 years (41-46) for 297 905 vaccinated individuals, with 260 tuberculosis episodes. Tuberculosis rates were 3·3 per 100 000 person-years in unvaccinated and 1·3 per 100 000 person-years in vaccinated individuals. The adjusted average VE during 40 year follow-up was 49% (95% CI 26-65), although after 20 years, the VE was not significant (up to 9 years VE [excluding tuberculosis episodes in the first 2 years] 61% [95% CI 24-80]; 10-19 years 58% [27-76]; 20-29 years 38% [-32 to 71]; 30-40 years 42% [-24 to 73]). VE against pulmonary tuberculosis up to 9 years (excluding tuberculosis episodes in the first 2 years) was 67% (95% CI 27-85), 10-19 years was 63% (32-80), 20-29 years was 50% (-19 to 79), and 30-40 years was 40% (-46 to 76). INTERPRETATION: Findings are consistent with long-lasting BCG protection, but waning of VE with time. The vaccine could be more cost effective than has been previously estimated FUNDING: Norwegian Institute of Public Health and London School of Hygiene & Tropical Medicine

Patient and health care system delays in the start of tuberculosis treatment in Norway

BACKGROUND: Delay in start of tuberculosis (TB) treatment has an impact at both the individual level, by increasing the risk of morbidity and mortality, and at the community level, by increasing the risk of transmission. The aims of this study were to assess the delays in the start of treatment for TB patients in Oslo/Akershus region, Norway and to analyze risk factors for the delays. METHODS: This study was based on information from the National TB Registry, clinical case notes from hospitals and referral case notes from primary health care providers. Delays were divided into patient, health care system and total delays. The association with sex, birthplace, site of the disease and age group was analyzed by multiple linear regression. RESULTS: Among the 83 TB patients included in this study, 71 (86%) were born abroad. The median patient, health care system and total delays were 28, 33 and 63 days respectively, with a range of 1–434 days. In unadjusted analysis, patient delay and health care system delay did not vary significantly between men and women, according to birthplace or age group. Patients with extra-pulmonary TB had a significantly longer patient, health care system and total delay compared to patients with pulmonary TB. Median total delay was 81 and 56 days in the two groups of TB patients respectively. The health care system delay exceeded the patient delay for those born in Norway. The age group 60+ years had significantly shorter patient delay than the reference group aged 15–29 years when adjusted for multiple covariates. Also, in the multivariate analysis patients born in Norway had significantly longer health care system delay than patients born abroad. CONCLUSION: A high proportion of patients had total delays in start of TB treatment exceeding two months. This study emphasizes the need of awareness of TB in the general population and among health personnel. Extra-pulmonary TB should be considered as a differential diagnosis in unresolved cases, especially for immigrants from high TB prevalence countries

Strong tuberculin response after BCG vaccination is associated with low multiple sclerosis risk: a population-based cohort study

Background: Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette–Guerin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk. Methods: Using data from a Norwegian tuberculosis screening programme (1963–1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship. Results: Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76–0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST. Conclusion: A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades.publishedVersio

Individual Variation in Adaptive Immune Responses and Risk of Hip Fracture-A NOREPOS Population-Based Cohort Study

Immune‐mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post‐vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette‐Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow‐up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01–1.44) and 24% (HR = 1.24, 95% CI 1.03–1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non‐significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune‐mediated bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

Screening for tuberculosis infection among newly arrived asylum seekers: Comparison of QuantiFERON®TB Gold with tuberculin skin test

Background: QuantiFERON®TB Gold (QFT) is a promising blood test for tuberculosis infection but with few data so far from immigrant screening. The aim of this study was to compare results of QFT and tuberculin skin test (TST) among newly arrived asylum seekers in Norway and to assess the role of QFT in routine diagnostic screening for latent tuberculosis infection. Methods: The 1000 asylum seekers (age ≥ 18 years) enrolled in the study were voluntarily recruited from 2813 consecutive asylum seekers arriving at the national reception centre from September 2005 to June 2006. Participation included a QFT test and a questionnaire in addition to the mandatory TST and chest X-ray. Results: Among 912 asylum seekers with valid test results, 29% (264) had a positive QFT test whereas 50% (460) tested positive with TST (indurations ≥ 6 mm), indicating a high proportion of latent infection within this group. Among the TST positive participants 50% were QFT negative, whereas 7% of the TST negative participants were QFT positive. There was a significant association between increase in size of TST result and the likelihood of being QFT positive. Agreement between the tests was 71–79% depending on the chosen TST cut-off and it was higher for nonvaccinated individuals. Conclusion: By using QFT in routine screening, further follow-up could be avoided in 43% of the asylum seekers who would have been referred if based only on a positive TST (≥ 6 mm). The proportion of individuals referred will be the same whether QFT replaces TST or is used as a supplement to confirm a positive TST, but the number tested will vary greatly. All three screening approaches would identify the same proportion (88–89%) of asylum seekers with a positive QFT and/or a TST ≥ 15 mm, but different groups will be missed

How many of persistent coughers have pulmonary tuberculosis? Populationbased cohort study in Ethiopia

Objective Many individuals with persistent cough and smear microscopy-negative sputum test for tuberculosis (TB) remain at risk of developing the disease. This study estimates the incidence of pulmonary TB (PTB) among initially smear-negative persistent coughers and its risk factors. Design A prospective population-based follow-up study. Setting Health extension workers visited all households in Dale woreda three times at 4-month intervals in 2016–2017 to identify individuals with symptoms compatible with TB (presumptive TB) using pretested and semistructured questionnaires. Participants We followed 3484 presumptive TB cases (≥15 years) with an initial smear-negative TB (PTB) test. Outcome measures Bacteriologically confirmed PTB (PTB b+) and clinically diagnosed PTB (PTB c+). Results 3484 persons with initially smear-negative presumptive PTB were followed for 2155 person-years (median 0.8 years); 90 individuals had PTB b+ and 90 had PTB c+. The incidence rates for PTB b+ and PTB c+ were both 4176 (95% CI 3378 to 5109) per 100 000 person-years. We used penalised (lasso) and non-penalised proportional hazards Cox regression models containing all exposures and outcomes to explore associations between exposures and outcomes. In lasso regression, the risk of development of PTB b+ was 63% (HR 0.37) lower for people aged 35–64 years and 77% (HR 0.23) lower for those aged ≥65 years compared with 15–34 year-olds. Men had a 62% (HR 1.62) greater risk of PTB b+ development than women. The risk of PTB c+ was 39% (HR 0.61) lower for people aged 35–54 years than for those aged 15–34 years. Men had a 56% (HR 1.56) greater risk of PTB c+ development than women. Conclusions PTB incidence rate among persistent coughers was high, especially among men and young adults, the latter signifying sustained transmission. Awareness about this among healthcare workers may improve identification of more new TB cases.publishedVersio

Treatment outcome of new culture positive pulmonary tuberculosis in Norway

BACKGROUND: The key elements in tuberculosis (TB) control are to cure the individual patient, interrupt transmission of TB to others and prevent the tubercle bacilli from becoming drug resistant. Incomplete treatment may result in excretion of bacteria that may also acquire drug resistance and cause increased morbidity and mortality. Treatment outcome results serves as a tool to control the quality of TB treatment provided by the health care system. The aims of this study were to evaluate the treatment outcome for new cases of culture positive pulmonary TB registered in Norway during the period 1996–2002 and to identify factors associated with non-successful treatment. METHODS: This was a register-based cohort study. Treatment outcome was assessed according to sex, birthplace, age group, isoniazid (INH) susceptibility, mode of detection and treatment periods (1996–1997, 1998–1999 and 2000–2002). Logistic regression was also used to estimate the odds ratio for treatment success vs. non-success with 95% confidence interval (CI), taking the above variables into account. RESULTS: Among the 655 patients included, the total treatment success rate was 83% (95% CI 80%–86%). The success rates for those born in Norway and abroad were 79% (95% CI 74%–84%) and 86% (95% CI 83%–89%) respectively. There was no difference in success rates by sex and treatment periods. Twenty-two patients (3%) defaulted treatment, 58 (9%) died and 26 (4%) transferred out. The default rate was higher among foreign-born and male patients, whereas almost all who died were born in Norway. The majority of the transferred out group left the country, but seven were expelled from the country. In the multivariate analysis, only high age and initial INH resistance remained as significant risk factors for non-successful treatment. CONCLUSION: Although the TB treatment success rate in Norway has increased compared to previous studies and although it has reached a reasonable target for treatment outcome in low-incidence countries, the total success rate for 1996–2002 was still slightly below the WHO target of success rate of 85%. Early diagnosis of TB in elderly patients to reduce the death rate, abstaining from expulsion of patients on treatment and further measures to prevent default could improve the success rate further

Treatment outcomes for isoniazid-monoresistant tuberculosis in Peru, 2012-2014.

BACKGROUND: Resistance to isoniazid is the most common form of drug-resistance in tuberculosis. However only a tiny proportion of TB patients in the world have access to isoniazid drug susceptibility testing-the widely implemented Xpert MTB/RIF technology only tests for resistance to rifampicin. Patients with isoniazid mono resistance that is not identified at baseline are treated with a standard regimen that effectively results in rifampicin mono-therapy during the latter four months of the six month treatment course, exposing remaining viable organisms to a single agent and greatly increasing the risk of development of multi drug-resistant TB. Unusually, Peru has pioneered universal pre-treatment drug susceptibility testing with methods that identify isoniazid resistance and has thus identified a large number of individuals requiring tailored therapy. Since 2010, treatment in Peru for isoniazid-resistant tuberculosis without multidrug-resistant tuberculosis (Hr-TB) has been with a standardized nine-month regimen of levofloxacin, rifampicin, ethambutol and pyrazinamide. The objectives of this study were to evaluate the outcomes of treatment for patients with Hr-TB initiating treatment with this regimen between January 2012 and December 2014 and to determine factors affecting these outcomes. METHODS: Retrospective cross-sectional study; case data were obtained from the national registry of drug-resistant tuberculosis. Patients diagnosed with isoniazid resistant TB without resistance to rifampicin, pyrazinamide, ethambutol and quinolones as determined by either a rapid drug susceptibility testing (DST) (nitrate reductase test, MODS, Genotype MTBDRplus) or by the proportion method were included. FINDINGS: A total of 947 cases were evaluated (a further 403 without treatment end date were excluded), with treatment success in 77.2% (731 cases), loss to follow-up in 19.7% (186 cases), treatment failure in 1.2% (12 cases), and death in 1.9% (18 cases). Unfavorable outcomes were associated in multivariate analysis with male gender (OR 0.50, 95% CI 0.34-0.72, p<0.05), lack of rapid DST (OR 0.67, 95% CI 0.50-0.91, p = 0.01), additional use of an injectable second-line anti-tuberculous drug (OR 0.46, 95% CI 0.31-0.70, p<0.05), and treatment initiation in 2014 (OR 0.77, 95% CI 0.62-0.94, p = 0.01). INTERPRETATION: The treatment regimen implemented in Peru for isoniazid resistant TB is effective for TB cure and is not improved by addition of an injectable second-line agent. Access to rapid DST and treatment adherence need to be strengthened to increase favorable results

Minimum package for cross-border TB control and care in the WHO European region: a Wolfheze consensus statement

The World Health Organization (WHO) European region estimates that more than 400,000 tuberculosis (TB) cases occur in Europe, a large proportion of them among migrants. A coordinated public health mechanism to guarantee TB prevention, diagnosis, treatment and care across borders is not in place. A consensus paper describing the minimum package of cross-border TB control and care was prepared by a task force following a literature review, and with input from the national TB control programme managers of the WHO European region and the Wolfheze 2011 conference. A literature review focused on the subject of TB in migrants was carried out, selecting documents published during the 11-yr period 2001–2011. Several issues were identified in cross-border TB control and care, varying from the limited access to early TB diagnosis, to the lack of continuity of care and information during migration, and the availability of, and access to, health services in the new country. The recommended minimum package addresses the current shortcomings and intends to improve the situation by covering several areas: political commitment (including the implementation of a legal framework for TB cross-border collaboration), financial mechanisms and adequate health service delivery (prevention, infection control, contact management, diagnosis and treatment, and psychosocial support).</br

Tuberculosis screening and follow-up of asylum seekers in Norway: a cohort study

<p>Abstract</p> <p>Background</p> <p>About 80% of new tuberculosis cases in Norway occur among immigrants from high incidence countries. On arrival to the country all asylum seekers are screened with Mantoux test and chest x-ray aimed to identify cases of active tuberculosis and, in the case of latent tuberculosis, to offer follow-up or prophylactic treatment.</p> <p>We assessed a national programme for screening, treatment and follow-up of tuberculosis infection and disease in a cohort of asylum seekers.</p> <p>Methods</p> <p>Asylum seekers ≥ 18 years who arrived at the National Reception Centre from January 2005 to June 2006, were included as the total cohort. Those with a Mantoux test ≥ 6 mm or positive x-ray findings were included in a study group for follow-up.</p> <p>Data were collected from public health authorities in the municipality to where the asylum seekers had moved, and from hospital based internists in case they had been referred to specialist care.</p> <p>Individual subjects included in the study group were matched with the Norwegian National Tuberculosis Register which receive reports of everybody diagnosed with active tuberculosis, or who had started treatment for latent tuberculosis.</p> <p>Results</p> <p>The total cohort included 4643 adult asylum seekers and 97.5% had a valid Mantoux test. At least one inclusion criterion was fulfilled by 2237 persons. By end 2007 municipal public health authorities had assessed 758 (34%) of them. Altogether 328 persons had been seen by an internist. Of 314 individuals with positive x-rays, 194 (62%) had seen an internist, while 86 of 568 with Mantoux ≥ 15, but negative x-rays (16%) were also seen by an internist. By December 31^st2006, 23 patients were diagnosed with tuberculosis (prevalence 1028/100 000) and another 11 were treated for latent infection.</p> <p>Conclusion</p> <p>The coverage of screening was satisfactory, but fewer subjects than could have been expected from the national guidelines were followed up in the community and referred to an internist. To improve follow-up of screening results, a simplification of organisation and guidelines, introduction of quality assurance systems, and better coordination between authorities and between different levels of health care are all required.</p