A Novel, High-sensitivity, Bacteriophage-based Assay Identifies Low-level Mycobacterium tuberculosis Bacteremia in Immunocompetent Patients With Active and Incipient Tuberculosis.

The haematogenous dissemination of Mycobacterium tuberculosis (Mtb) is critical to the pathogenesis of progressive tuberculous infections in animal models. Using a novel, phage-based blood assay, we report the first concordant evidence in well-characterized, immunocompetent human cohorts, demonstrating associations of Mtb bacteremia with progressive phenotypes of latent infection and active pulmonary tuberculosis.

A nested case-control study of predictors for tuberculosis recurrence in a large UK Centre.

BACKGROUND: Tuberculosis (TB) recurrence represents a challenge to control programs. In low incidence countries, the prevailing risk factors leading to recurrence are poorly characterised. METHODS: We conducted a nested case-control study using the Leicester TB service TBIT database. Cases were identified from database notifications between 1994 and 2014. Controls had one episode and were matched to cases on a ratio of two to one by the date of notification. Multiple imputation was used to account for missing data. Multivariate conditional logistic regression analysis was employed to identify clinical, sociodemographic and TB specific risk factors for recurrence. RESULTS: From a cohort of 4628 patients, 82 TB recurrences occurred (1.8%). Nineteen of 82 patients had paired isolates with MIRU-VNTR strain type profiles available, of which 84% were relapses and 16% reinfections. On multivariate analysis, smoking (OR 3.8; p = 0.04), grade 3/4 adverse drug reactions (OR 5.6; p = 0.02), ethnicity 'Indian subcontinent' (OR 8.5; p = <0.01), ethnicity 'other' (OR 31.2; p = 0.01) and receipt of immunosuppressants (OR 6.8; p = <0.01) were independent predictors of TB recurrence. CONCLUSIONS: Within this UK setting, the rate of TB recurrence was low, predominantly due to relapse. The identification of an elevated recurrence risk amongst the ethnic group contributing most cases to the national TB burden presents an opportunity to improve individual and population health.

Pulmonary Diseases in Refugees and Migrants in Europe.

More than 2 million people fleeing conflict, persecution, and poverty applied for asylum between 2015 and 2016 in the European Union. Due to this, medical practitioners in recipient countries may be facing a broader spectrum of conditions and unusual presentations not previously encountered, including a wide range of infections with pulmonary involvement. Tuberculosis is known to be more common in migrants and has been covered broadly in other publications. The scope of this review was to provide an overview of exotic infections with pulmonary involvement that could be encountered in refugees and migrants and to briefly describe their epidemiology, diagnosis, and management. As refugees and migrants travel from numerous countries and continents, it is important to be aware of the various organisms that might cause disease according to the country of origin. Some of these diseases are very rare and geographically restricted to certain regions, while others have a more cosmopolitan distribution. Also, the spectrum of severity of these infections can vary from very benign to severe and even life-threatening. We will also describe infectious and noninfectious complications that can be associated with HIV infection as some migrants might originate from high HIV prevalence countries in sub-Saharan Africa. As the diagnosis and treatment of these diseases can be challenging in certain situations, patients with suspected infection might require referral to specialized centers with experience in their management. Additionally, a brief description of noncommunicable pulmonary diseases will be provided.

Phenotypically Adapted Mycobacterium tuberculosis Populations from Sputum Are Tolerant to First-Line Drugs.

Tuberculous sputum contains multipleMycobacterium tuberculosispopulations with different requirements for isolationin vitro These include cells that form colonies on solid media (plateableM. tuberculosis), cells requiring standard liquid medium for growth (nonplateableM. tuberculosis), and cells requiring supplementation of liquid medium with culture supernatant (SN) for growth (SN-dependentM. tuberculosis). Here, we describe protocols for the cryopreservation and direct assessment of antimicrobial tolerance of theseM. tuberculosispopulations within sputum. Our results show that first-line drugs achieved only modest bactericidal effects on all three populations over 7 days (1 to 2.5 log10reductions), and SN-dependentM. tuberculosiswas more tolerant to streptomycin and isoniazid than the plateable and nonplateableM. tuberculosisstrains. Susceptibility of plateableM. tuberculosisto bactericidal drugs was significantly increased after passagein vitro; thus, tolerance observed in the sputum samples from the population groups was likely associated with mycobacterial adaptation to the host environment at some time prior to expectoration. Our findings support the use of a simpleex vivosystem for testing drug efficacies against mycobacteria that have phenotypically adapted during tuberculosis infection.

Vitamin D deficiency and TB disease phenotype.

BACKGROUND: Extrapulmonary TB is increasingly common, yet the determinants of the wide clinical spectrum of TB are poorly understood. METHODS: We examined surveillance data (Birmingham, UK: 1980-2009 and USA Centers for Disease Control: 1993-2008) to identify demographic factors associated with extrapulmonary TB. We then directly tested association of these factors and serum 25-hydroxycholecalciferol (25(OH)D) concentration with extrapulmonary TB by multivariable analysis in a separate UK cohort. RESULTS: Data were available for 10,152 and 277,013 TB cases for Birmingham and US, respectively. Local-born individuals of white ethnicity had a lower proportion of extrapulmonary disease when compared with local-born non-whites (p<0.0001); both groups had a lower proportion of extrapulmonary disease when compared with foreign-born non-whites (p<0.0001). In a separate UK cohort (n=462), individuals with extrapulmonary TB had lower mean serum 25(OH)D concentration than those with pulmonary TB (11.4 vs 15.2 nmol/L, respectively, p=0.0001). On multivariable analysis, vitamin D deficiency was strongly associated with extrapulmonary TB independently of ethnicity, gender and other factors. Doubling in serum 25(OH)D concentration conferred substantially reduced risk of extrapulmonary disease (OR 0.55, 95% CI 0.41 to 0.73). CONCLUSIONS: We identify vitamin D deficiency as a probable risk factor for extrapulmonary dissemination in TB, which may account for the associations of dark-skinned ethnicity and female gender with extrapulmonary disease. Our findings implicate vitamin D status in Mycobacterium tuberculosis containment in vivo and, given the high prevalence of deficiency, may inform development of novel TB prevention strategies.

The effectiveness of primary care based risk stratification for targeted latent tuberculosis infection screening in recent immigrants to the UK: a retrospective cohort study.

BACKGROUND: Most UK tuberculosis (TB) cases occur in immigrants from high TB incidence areas, implicating reactivation of imported latent TB infection (LTBI). Strategies to identify and treat immigrant LTBI in primary care at the time of first registration (coded Flag-4) may be effective. METHODS: This was an 11-year retrospective cohort study to evaluate effectiveness of LTBI screening in recent immigrants to Leicestershire at their time of primary care registration. We examined the temporal relationship between dates of Flag-4 primary care registration (n=59 007) and foreign-born TB (FB-TB) cases (n=857), for immigrants arriving to the UK after 1999. TB diagnosed >6 months after registration was considered potentially preventable with screening. Primary outcomes were the potentially preventable proportion of FB-TB and the number needed to screen (NNS) of immigrants to identify one potentially preventable case, stratified by age and region of origin. RESULTS: 250 cases (29%) were potentially preventable in Flag-4-registered immigrants. Overall, 511 cases (60%) were potentially preventable among primary-care registered immigrants, implying a significant proportion without Flag-4 status. Prospective TB incidence (95% CI) after Flag-4 registration was 183 (163 to 205) cases/100 000 person-years, with a NNS (95% CI) of 145 (130 to 162). Targeted screening was most effective for 16-35 year olds from TB incidence regions 150-499/100 000 (NNS (95% CI)=65 (57 to 74), preventing 159 (18.7%) cases). Unpreventable TB risk increased with delayed primary care registration after UK entry (p<0.001) and was associated with HIV seropositivity (relative risk (95% CI)=1.89 (1.25 to 2.84), p=0.003). CONCLUSIONS: LTBI screening at primary care registration offers an effective strategy for potentially identifying immigrants at high risk of developing TB.

Prognostication of co-morbidity clusters on hospitalisation and mortality in advanced COPD.

RATIONALE: As the prevalence of multimorbidity increases, understanding the impact of isolated comorbidities in people COPD becomes increasingly challenging. A simplified model of common comorbidity patterns may improve outcome prediction and allow targeted therapy. OBJECTIVES: To assess whether comorbidity phenotypes derived from routinely collected clinical data in people with COPD show differences in risk of hospitalisation and mortality. METHODS: Twelve clinical measures related to common comorbidities were collected during annual reviews for people with advanced COPD and k-means cluster analysis performed. Cox proportional hazards with adjustment for covariates was used to determine hospitalisation and mortality risk between clusters. MEASUREMENTS AND MAIN RESULTS: In 203 participants (age 66 ± 9 years, 60 % male, FEV1%predicted 31 ± 10 %) no comorbidity in isolation was predictive of worse admission or mortality risk. Four clusters were described: cluster A (cardiometabolic and anaemia), cluster B (malnourished and low mood), cluster C (obese, metabolic and mood disturbance) and cluster D (less comorbid). FEV1%predicted did not significantly differ between clusters. Mortality risk was higher in cluster A (HR 3.73 [95%CI 1.09-12.82] p = 0.036) and B (HR 3.91 [95%CI 1.17-13.14] p = 0.027) compared to cluster D. Time to admission was highest in cluster A (HR 2.01 [95%CI 1.11-3.63] p = 0.020). Cluster C was not associated with increased risk of mortality or hospitalisation. CONCLUSIONS: Despite presence of advanced COPD, we report striking differences in prognosis for both mortality and hospital admissions for different co-morbidity phenotypes. Objectively assessing the multi-system nature of COPD could lead to improved prognostication and targeted therapy for patients.

PET-CT-guided characterisation of progressive, preclinical tuberculosis infection and its association with low-level circulating Mycobacterium tuberculosis DNA in household contacts in Leicester, UK: a prospective cohort study.

BACKGROUND: Incipient tuberculosis, a progressive state of Mycobacterium tuberculosis infection with an increased risk of developing into tuberculosis disease, remains poorly characterised. Animal models suggest an association of progressive infection with bacteraemia. Circulating M tuberculosis DNA has previously been detected in pulmonary tuberculosis by use of Actiphage, a bacteriophage-based real-time PCR assay. We aimed to investigate whether serial [18F]fluorodeoxyglucose ([18F]FDG)-PET-CT could be used to characterise the state and progressive trajectory of incipient tuberculosis, and examine whether these PET-CT findings are associated with Actiphage-based detection of circulating M tuberculosis DNA. METHODS: We did a prospective 12-month cohort study in healthy, asymptomatic adults (aged ≥16 years) who were household contacts of patients with pulmonary tuberculosis, and who had a clinical phenotype of latent tuberculosis infection, in Leicester, UK. Actiphage testing of participants' blood samples was done at baseline, and [18F]FDG PET-CT at baseline and after 3 months. Baseline PET-CT features were classified as positive, indeterminate, or negative, on the basis of the quantitation (maximum standardised uptake value [SUVmax]) and distribution of [18F]FDG uptake. Microbiological sampling was done at amenable sites of [18F]FDG uptake. Changes in [18F]FDG uptake after 3 months were quantitatively categorised as progressive, stable, or resolving. Participants received treatment if features of incipient tuberculosis, defined as microbiological detection of M tuberculosis or progressive PET-CT change, were identified. FINDINGS: 20 contacts were recruited between Aug 5 and Nov 5, 2020; 16 of these participants had a positive result on IFNγ release assay (QuantiFERON-TB Gold Plus [QFT]) indicating tuberculosis infection. Baseline PET-CT scans were positive in ten contacts (all QFT positive), indeterminate in six contacts (three QFT positive), and negative in four contacts (three QFT positive). Four of eight PET-CT-positive contacts sampled had M tuberculosis identified (three through culture, one through Xpert MTB/RIF Ultra test) from intrathoracic lymph nodes or bronchial wash and received full antituberculosis treatment. Two further unsampled PET-CT-positive contacts were also treated: one with [18F]FDG uptake in the lung (SUVmax 9·4) received empirical antituberculosis treatment and one who showed progressive [18F]FDG uptake received preventive treatment. The ten untreated contacts with [18F]FDG uptake at baseline (seven QFT positive) had stable or resolving changes at follow-up and remained free of tuberculosis disease after 12 months. A positive baseline Actiphage test was associated with the presence of features of incipient tuberculosis requiring treatment (p=0·018). INTERPRETATION: Microbiological and inflammatory features of incipient tuberculosis can be visualised on PET-CT and are associated with M tuberculosis detection in the blood, supporting the development of pathogen-directed blood biomarkers of tuberculosis risk. FUNDING: MRC Confidence in Concept.

Interferon-gamma release assay conversion after Mycobacterium tuberculosis exposure specifically associates with greater risk of progression to tuberculosis: A prospective cohort study in Leicester, UK.

OBJECTIVES: We investigated whether quantifying the serial QuantiFERON-TB Gold (QFT) response improves tuberculosis (TB) risk stratification in pulmonary TB (PTB) contacts. METHODS: A total of 297 untreated adult household PTB contacts, QFT tested at baseline and 3 months after index notification, were prospectively observed (median 1460 days). Normal variance of serial QFT responses was established in 46 extrapulmonary TB contacts. This informed categorisation of the response in QFT-positive PTB contacts as converters, persistently QFT-positive with significant increase (PPincrease), and without significant increase (PPno-increase). RESULTS: In total, eight co-prevalent TB (disease ≤3 months after index notification) and 12 incident TB (>3 months after index notification) cases were diagnosed. Genetic linkage to the index strain was confirmed in all culture-positive progressors. The cumulative 2-year incident TB risk in QFT-positive contacts was 8.4% (95% confidence interval, 3.0-13.6%); stratifying by serial QFT response, significantly higher risk was observed in QFT converters (28%), compared with PPno-increase (4.8%) and PPincrease (3.7%). Converters were characterised by exposure to index cases with a shorter interval from symptom onset to diagnosis (median reduction 50.0 days, P = 0.013). CONCLUSIONS: QFT conversion, rather than quantitative changes of a persistently positive serial QFT response, is associated with greater TB risk and exposure to rapidly progressive TB.

Single-step QuantiFERON screening of adult contacts: a prospective cohort study of tuberculosis risk.

BACKGROUND: The efffectiveness of tuberculosis (TB) contact screening programmes using interferon γ release assays remains uncertain as prospective contact TB risk is not well characterised. OBJECTIVES: To quantify 2-year TB risk and evaluate screening performance with single-step QuantiFERON TB Gold-In Tube (QFT) in adult contacts. To compare TB risk between QFT tested subgroups stratified by exposure type (smear positive pulmonary (SP) versus non-smear positive (NSP) TB) and age (younger (16-35 years) versus older (≥36 years)). METHODS: Screening involved QFT testing in older contacts of SP and all younger contacts, 8-12 weeks after index notification. Chemoprevention (3RH) was offered to QFT positive (+) younger adults. TB risk was determined in a prospective cohort study. RESULTS: 43 TB events occurred in 1769 adult contacts observed for median 717 days (2-year rate (95% CI)=2·5% (1.7 to 3.2)). Index-contact strain matching was demonstrable for 18 of 22 (82%) paired samples. No contacts (0/98) receiving 3RH developed TB. 215 of 817 appropriately tested adults (26.3%) were QFT+. 14 of 112 untreated QFT+ adults developed TB (2-year rate (95% CI)=13·4% (7.7 to 21.1)). The model required 35 contacts screened with QFT to identify one contact developing TB at 2 years. TB rates were comparable in QFT+ contacts of SP and NSP (rate ratio (RR)=0.98, p=0·962). For QFT+ older contacts, the disease rate was lower (8.9% (3.3 to 19.1)) and similar to the overall group rate (RR=1.4, p=0.503). CONCLUSIONS: QFT based single-step contact screening is effective in young adults.

A data-driven framework for clinical decision support applied to pneumonia management.

Despite their long history, it can still be difficult to embed clinical decision support into existing health information systems, particularly if they utilise machine learning and artificial intelligence models. Moreover, when such tools are made available to healthcare workers, it is important that the users can understand and visualise the reasons for the decision support predictions. Plausibility can be hard to achieve for complex pathways and models and perceived "black-box" functionality often leads to a lack of trust. Here, we describe and evaluate a data-driven framework which moderates some of these issues and demonstrate its applicability to the in-hospital management of community acquired pneumonia, an acute respiratory disease which is a leading cause of in-hospital mortality world-wide. We use the framework to develop and test a clinical decision support tool based on local guideline aligned management of the disease and show how it could be used to effectively prioritise patients using retrospective analysis. Furthermore, we show how this tool can be embedded into a prototype clinical system for disease management by integrating metrics and visualisations. This will assist decision makers to examine complex patient journeys, risk scores and predictions from embedded machine learning and artificial intelligence models. Our results show the potential of this approach for developing, testing and evaluating workflow based clinical decision support tools which include complex models and embedding them into clinical systems.

Neurogenic Pulmonary Edema Presenting as a Pulmonary Entity.

Acute dyspnea is one of the most common presentations in acute/emergency settings, and acute pulmonary edema remains a leading cause in adults resulting from either cardiogenic or non-cardiogenic etiologies. Neurogenic pulmonary edema (NPE) is one of the less common forms of non-cardiogenic pulmonary edema seen in emergency departments, neurology units, or intensive care units. It usually develops rapidly following significant neurological insult seen in patients with intracranial hemorrhage, traumatic brain injuries, and epileptic seizures. It is less commonly seen after a multitude of other sudden catastrophic neurologic insults. Here, we report a case study of a 32-year-old female with a history of epilepsy since childhood who was admitted to our respiratory admission unit on two separate occasions with acute NPE and type I respiratory failure after a witnessed tonic-clonic seizure episode. Although the clinical features of NPE and the results of investigations can mimic more common cardiorespiratory conditions, an accurate and timely diagnosis is vital for the appropriate emergency management and to improve the patient's outcome.

A Persistent Tuberculosis Outbreak in the UK Is Characterized by Hydrophobic fadB4-Deficient Mycobacterium tuberculosis That Replicates Rapidly in Macrophages.

The genetic diversity of Mycobacterium tuberculosis can influence disease severity and transmissibility. To better understand how this diversity influences individuals and communities, we phenotyped M. tuberculosis that was causing a persistent outbreak in the East Midlands, United Kingdom. Compared to nonoutbreak isolates, bacilli had higher lipid contents and more hydrophobic cell surfaces. In macrophage infection models, the bacteria increased more rapidly, provoked the enhanced accumulation of macrophage lipid droplets and enhanced the secretion of IL-1ß. Natural deletions in fadB4, nrdB, and plcC distinguished the outbreak isolates from other lineage 3 isolates in the region. fadB4 is annotated with a putative role in cell envelope biosynthesis, so the loss of this gene has the potential to alter the interactions of bacteria with immune cells. Reintroduction of fadB4 to the outbreak strain led to a phenotype that more closely resembled those of nonoutbreak strains. The improved understanding of the microbiological characteristics and the corresponding genetic polymorphisms that associate with outbreaks have the potential to inform tuberculosis control. IMPORTANCE Tuberculosis (TB) killed 1.5 million people in 2020 and affects every country. The extent to which the natural genetic diversity of Mycobacterium tuberculosis influences disease manifestation at both the individual and epidemiological levels remains poorly understood. Insights into how pathogen polymorphisms affect patterns of TB have the potential to translate into clinical and public health practice. Two distinct lineage 3 strains isolated from local TB outbreaks, one of which (CH) was rapidly terminated and the other of which (Lro) persistently transmitted for over a decade, provided us with an opportunity to study these issues. We compared genome sequences, microbiological characteristics, and early immune responses that were evoked upon infection. Our results indicate that the natural lack of fadB4 in the Lro strain contributes to its unique features.

Resuscitation-promoting factors reveal an occult population of tubercle Bacilli in Sputum.

RATIONALE: Resuscitation-promoting factors (Rpfs) are a family of secreted proteins produced by Mycobacterium tuberculosis (Mtb) that stimulate mycobacterial growth. Although mouse infection studies show that they support bacterial survival and disease reactivation, it is currently unknown whether Rpfs influence human infection. We hypothesized that tuberculous sputum might include a population of Rpf-dependent Mtb cells. OBJECTIVES: To determine whether Rpf-dependent Mtb cells are present in human sputum and explore the impact of chemotherapy on this population. METHODS: In tuberculous sputum samples we compared the number of cells detected by conventional agar colony-forming assay with that determined by limiting dilution, most-probable number assay in the presence or absence of Rpf preparations. MEASUREMENTS AND MAIN RESULTS: In 20 of 25 prechemotherapy samples from separate patients, 80-99.99% of the cells demonstrated by cultivation could be detected only with Rpf stimulation. Mtb cells with this phenotype were not generated on specimen storage or by inoculating sputum samples with a selection of clinical isolates; moreover, Rpf dependency was lost after primary isolation. During chemotherapy, the proportion of Rpf-dependent cells was found to increase relative to the surviving colony-forming population. CONCLUSIONS: Smear-positive sputum samples are dominated by a population of Mtb cells that can be grown only in the presence of Rpfs. These intriguing proteins are therefore relevant to human infection. The Rpf-dependent population is invisible to conventional culture and is progressively enhanced in relative terms during chemotherapy, indicating a form of phenotypic resistance that may be significant for both chemotherapy and transmission.

Tuberculosis in UK cities: workload and effectiveness of tuberculosis control programmes.

BACKGROUND: Tuberculosis (TB) has increased within the UK and, in response, targets for TB control have been set and interventions recommended. The question was whether these had been implemented and, if so, had they been effective in reducing TB cases. METHODS: Epidemiological data were obtained from enhanced surveillance and clinics. Primary care trusts or TB clinics with an average of > 100 TB cases per year were identified and provided reflections on the reasons for any change in their local incidence, which was compared to an audit against the national TB plan. RESULTS: Access to data for planning varied (0-22 months). Sputum smear status was usually well recorded within the clinics. All cities had TB networks, a key worker for each case, free treatment and arrangements to treat HIV co-infection. Achievement of targets in the national plan correlated well with change in workload figures for the commissioning organizations (Spearman's rank correlation R = 0.8, P < 0.01) but not with clinic numbers. Four cities had not achieved the target of one nurse per 40 notifications (Birmingham, Bradford, Manchester and Sheffield). Compared to other cities, their loss to follow-up during treatment was usually > 6% (χ2 = 4.2, P < 0.05), there was less TB detected by screening and less outreach. Manchester was most poorly resourced and showed the highest rate of increase of TB. Direct referral from radiology, sputum from primary care and outreach workers were cited as important in TB control. CONCLUSION: TB control programmes depend on adequate numbers of specialist TB nurses for early detection and case-holding.Please see related article: http://www.biomedcentral.com/1741-7015/9/127.

Clinical utility of a rapid 'on-demand' laboratory-based SARS-CoV-2 diagnostic testing service in an acute hospital setting admitting COVID-19 patients.

BACKGROUND: With the onset of the COVID-19 pandemic in 2020, hospital clinical teams have realised that there is a need for a rapid, accurate testing facility that will allow them to move patients quickly into isolation rooms or specific COVID-19 cohort wards as soon as possible after admission. METHODS: Starting from July 2020, PCR-based test platforms, which could test 4-8 samples in parallel with turnaround (sample-to-result) times of 50-80 min, were placed in a satellite laboratory. This laboratory was on the same floor and within walking distance to the acute respiratory admissions ward. It was staffed by a team of three mid-Band 4 staff that split a 0700-2200 h-work day, 7 days a week, with 2 senior supervisors. Urgent sample testing was decided upon by the clinical teams and requested by phone. The test results were entered manually in real-time as they became available, and sent electronically to the requesting ward teams. RESULTS: The daily/monthly PCR positive test numbers approximately followed the local and national UK trend in COVID-19 case numbers, with the daily case numbers being reflective of the November and December 2020 surges. Test results were used to rapidly segregate positive patients into dedicated COVID-19 ward areas to minimise risk of potential nosocomial transmission in crowded waiting areas. Testing capacity was sufficient to include cases with uncertain diagnosis likely to require hospital admission. Following completion of other admission processes, based on these rapid test results, patients were allocated to dedicated COVID-19 positive or negative cohort wards. CONCLUSIONS: This rapid testing facility reduced unnecessary 'length-of-stay' in a busy acute respiratory ward. In the current absence of a treatment for mild-to-moderate COVID-19, on which patients could be discharged home to complete, the rapid test facility has become a successful aid to patient flow and reduced exposure and nosocomial transmission.

Specialist pneumonia intervention nurse service improves pneumonia care and outcome.

BACKGROUND: A specialist pneumonia intervention nursing (SPIN) service was set up across a single National Health Service Trust in an effort to improve clinical outcomes. A quality improvement evaluation was performed to assess the outcomes associated with implementing the service before (2011-2013) and after (2014-2016) service implementation. RESULTS: The SPIN service reviewed 38% of community-acquired pneumonia (CAP) admissions in 2014-2016. 82% of these admissions received antibiotic treatment in <4 hours (68.5% in the national audit). Compared with the pre-SPIN period, there was a significant reduction in both 30-day (OR=0.77 (0.70-0.85), p<0.0001) and in-hospital (OR=0.66 (0.60-0.73), p<0.0001) mortality after service implementation, with a review by the service showing the largest independent 30-day mortality benefit (HR=0.60 (0.53-0.67), p<0.0001). There was no change in length of stay (median 6 days). CONCLUSION: Implementation of a SPIN service improved adherence to BTS guidelines and achieved significant reductions in CAP-associated mortality. This enhanced model of care is low cost, highly effective and readily adoptable in secondary care.

Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis.

Blood transcriptomics have revealed major characteristics of the immune response in active TB, but the signature early after infection is unknown. In a unique clinically and temporally well-defined cohort of household contacts of active TB patients that progressed to TB, we define minimal changes in gene expression in incipient TB increasing in subclinical and clinical TB. While increasing with time, changes in gene expression were highest at 30 d before diagnosis, with heterogeneity in the response in household TB contacts and in a published cohort of TB progressors as they progressed to TB, at a bulk cohort level and in individual progressors. Blood signatures from patients before and during anti-TB treatment robustly monitored the treatment response distinguishing early and late responders. Blood transcriptomics thus reveal the evolution and resolution of the immune response in TB, which may help in clinical management of the disease.