Summary Legionnaires' disease is an important cause of community-acquired and hospital-acquired pneumonia. Although uncommon, Legionnaires' disease continues to cause disease outbreaks of public ...health significance. The disease is caused by any species of the Gram-negative aerobic bacteria belonging to the genus Legionella ; Legionella pneumophila serogroup 1 is the causative agent of most cases in Europe. In this Review we outline the global epidemiology of Legionnaires' disease, summarise its diagnosis and management, and identify research gaps and priorities. Early clinical diagnosis and prompt initiation of appropriate antibiotics for Legionella spp in all patients with community-acquired or hospital-acquired pneumonias is a crucial measure for management of the disease. Progress in typing and sequencing technologies might additionally contribute to understanding the distribution and natural history of Legionnaires' disease, and inform outbreak investigations. Control of Legionnaires' disease outbreaks relies on rapid ascertainment of descriptive epidemiological data, combined with microbiological information to identify the source and implement control measures. Further research is required to define the actual burden of disease, factors that influence susceptibility, key sources of infection, and differences in virulence between strains of Legionella species. Other requirements are improved, specific, sensitive, and rapid diagnostic tests to accurately inform management of Legionnaires' disease, and controlled clinical trials to ascertain the optimum antibiotics for treatment.
Summary About 1·3 million people died of tuberculosis in 2012, despite availability of effective drug treatment. Barriers to improvements in outcomes include long treatment duration (resulting in ...poor patient adherence and loss of patients to follow-up), complex regimens that involve expensive and toxic drugs, toxic effects when given with antiretroviral therapy, and multidrug resistance. After 50 years of no antituberculosis drug development, a promising pipeline is emerging through the repurposing of old drugs, re-engineering of existing antibacterial compounds, and discovery of new compounds. A range of novel antituberculosis drugs are in preclinical development, several phase 2 and 3 trials are underway, and use of adjunct therapies is being explored for drug-sensitive and drug-resistant tuberculosis. Historical advances include approval of two new drugs, delamanid and bedaquiline. Combinations of new and existing drugs are being assessed to shorten the duration of therapy and to treat multidrug-resistant tuberculosis. There has also been progress in development of new antituberculosis drugs that are active against dormant or persister populations of Mycobacterium tuberculosis . In this Review, we discuss recent advances in antituberculosis drug discovery and development, clinical trial designs, laboratory methods, and adjunct host-directed therapies, and we provide an update of phase 3 trials of various fluoroquinolones (RIFAQUIN, NIRT, OFLOTUB, and REMoxTB). We also emphasise the need to engage the community in design, implementation, and uptake of research, to increase international cooperation between drug developers and health-care providers adopting new regimens.
Summary 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.
Summary Molecular data are now widely used in epidemiological studies to investigate the transmission, distribution, biology, and diversity of pathogens. Our objective was to establish ...recommendations to support good scientific reporting of molecular epidemiological studies to encourage authors to consider specific threats to valid inference. The statement Strengthening the Reporting of Molecular Epidemiology for Infectious Diseases (STROME-ID) builds upon the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative. The STROME-ID statement was developed by a working group of epidemiologists, statisticians, bioinformaticians, virologists, and microbiologists with expertise in control of infection and communicable diseases. The statement focuses on issues relating to the reporting of epidemiological studies of infectious diseases using molecular data that were not addressed by STROBE. STROME-ID addresses terminology, measures of genetic diversity within pathogen populations, laboratory methods, sample collection, use of molecular markers, molecular clocks, timeframe, multiple-strain infections, non-independence of infectious-disease data, missing data, ascertainment bias, consistency between molecular and epidemiological data, and ethical considerations with respect to infectious-disease research. In total, 20 items were added to the 22 item STROBE checklist. When used, the STROME-ID recommendations should advance the quality and transparency of scientific reporting, with clear benefits for evidence reviews and health-policy decision making.
Summary Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis ...face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment.
Summary Unacceptable levels of Mycobacterium tuberculosis transmission are noted in high burden settings and a renewed focus on reducing person-to-person transmission in these communities is needed. ...We review recent developments in the understanding of airborne transmission. We outline approaches to measure transmission in populations and trials and describe the Wells–Riley equation, which is used to estimate transmission risk in indoor spaces. Present research priorities include the identification of effective strategies for tuberculosis infection control, improved understanding of where transmission occurs and the transmissibility of drug-resistant strains, and estimates of the effect of HIV and antiretroviral therapy on transmission dynamics. When research is planned and interventions are designed to interrupt transmission, resource constraints that are common in high burden settings—including shortages of health-care workers—must be considered.
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 Accelerating progress in the fight against tuberculosis will require a drastic shift from a strategy focused on control to one focused on elimination. Successful disease elimination campaigns ...are characterised by locally tailored responses that are informed by appropriate data. To develop such a response to tuberculosis, we suggest a three-step process that includes improved collection and use of existing programmatic data, collection of additional data (eg, geographic information, drug resistance, and risk factors) to inform tailored responses, and targeted collection of novel data (eg, sequencing data, targeted surveys, and contact investigations) to improve understanding of tuberculosis transmission dynamics. Development of a locally targeted response for tuberculosis will require substantial investment to reconfigure existing systems, coupled with additional empirical data to evaluate the effectiveness of specific approaches. Without adoption of an elimination strategy that uses local data to target hotspots of transmission, ambitious targets to end tuberculosis will almost certainly remain unmet.
Summary We assess risks of communicable diseases that are associated with mass gatherings (MGs), outline approaches to risk assessment and mitigation, and draw attention to some key challenges ...encountered by organisers and participants. Crowding and lack of sanitation at MGs can lead to the emergence of infectious diseases, and rapid population movement can spread them across the world. Many infections pose huge challenges to planners of MGs; however, these events also provide an opportunity to engage in public health action that will benefit host communities and the countries from which participants originate.
Summary Background Several high-income countries have pre-entry screening programmes for tuberculosis. We aimed to establish the yield of pre-entry screening programmes to inform evidence-based ...policy for migrant health screening. Methods We searched six bibliographic databases for experimental or observational studies and systematic reviews, which reported data on migrant screening for active or latent tuberculosis by any method before migration to a low-incidence country. Primary outcomes were principal reported screening yield of active tuberculosis, yield of culture-confirmed cases, and yield of sputum smear for acid-fast bacilli cases. Where appropriate, fixed-effects models were used to summarise the yield of pre-entry screening across included studies. Findings We identified 15 unique studies with data for 3 739 266 migrants screened pre-entry for tuberculosis between 1982 and 2010. Heterogeneity was high for all primary outcomes. After stratification by prevalence in country of origin, heterogeneity was reduced for culture-confirmed and smear-confirmed cases. Yield of culture-confirmed cases increased with prevalence in the country of origin, and summary estimates ranged from 19·7 (95% CI 10·3–31·5) cases identified per 100 000 individuals screened in countries with a prevalence of 50–149 cases per 100 000 population to 335·9 (283·0–393·2) per 100 000 in countries with a prevalence of greater than 350 per 100 000 population. Interpretation Targeting high-prevalence countries could result in the highest yield for active disease. Pre-entry screening should be considered as part of a broad package of measures to ensure early diagnosis and effective management of migrants with active tuberculosis, and be integrated with initiatives that address the health needs of migrants. Funding Wellcome Trust, UK National Institute for Health Research, Medical Research Council, Public Health England.
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